1,5,7-Trisubstituted benzimidazole derivatives and their use for modulating the gabaa receptor complex

ABSTRACT

This invention relates to novel 1,5,7-trisubstituted benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith.  
     The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA A  receptor complex.

TECHNICAL FIELD

This invention relates to novel 1,5,7-trisubstituted benzimidazolederivatives pharmaceutical compositions containing these compounds, andmethods of treatment therewith.

The compounds of the invention are useful in the treatment of centralnervous system diseases and disorders, which are responsive tomodulation of the GABA_(A) receptor complex, and in particular forcombating anxiety and related diseases.

Background Art

The modulatory sites on the GABA_(A) receptor complex, such as forexample the benzodiazepine receptor, are the target for anxiolyticdrugs, such as the classical anxiolytic benzodiazepines. Multipleisoforms of the GABA_(A) receptor exist; each receptor is a pentamericcomplex comprising subunits drawn from α₁₋₆, β₁₋₃, γ₁₋₃, δ, ε, and θsubunit isoforms.

EP 616807 describes benzimidazole compounds for use as benzodiazepinereceptor ligands. Furthermore, the five compounds7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,7-(3-Pyridyl)-1-phenyl-5trifluoromethylbenzimidazole,1,7-Diphenyl-5-trifluoromethylbenzimidazole,7-benzoylamino-1-phenyl-5-trifluoro-methylbenzimidazole, and7-amino-1-phenyl-5-trifluoromethylbenzimidazole are disclosed therein asintermediates. No pharmaceutical use of these compounds are disclosed.

WO 96/33194, WO 96/33191 and WO 96/33192 describe benzimidazolecompounds having affinity for the GABA receptor complex.

WO 98/34923 describes phenylbenzimidazole derivatives as ligands for theGABA receptor complex.

WO 98/17651 and WO 00/78728 describe benzimidazole compounds for use ase.g. anaesthetics.

However, there is a continued strong need to find compounds with anoptimised biochemical profile. Furthermore, there is a strong need tofind effective compounds without unwanted side effects.

SUMMARY OF THE INVENTION

In its first aspect, the present invention provides compound of formulaI:

or an N-oxide thereof, or any of its isomers or any mixture of itsisomers, or a pharmaceutically acceptable salt thereof, wherein R⁵ andR⁷ are as defined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, or an N-oxide thereof, or any of its isomers or anymixture of its isomers, or a pharmaceutically acceptable salt thereof,together with at least one pharmaceutically acceptable carrier,excipient or diluent.

In a further aspect, the invention provides the use of a compound of theinvention, or an N-oxide thereof, or any of its isomers or any mixtureof its isomers, or a pharmaceutically acceptable salt thereof, for themanufacture of a pharmaceutical composition for the treatment,prevention or alleviation of a disease or a disorder or a condition of amammal, including a human, which disease, disorder or condition isresponsive to modulation of the GABA_(A) receptor complex in the centralnervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to modulation of the GABA_(A)receptor complex in the central nervous system, which method comprisesthe step of administering to such a living animal body in need thereof atherapeutically effective amount of a compound of the invention, or anN-oxide thereof, or any of its isomers or any mixture of its isomers, ora pharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

1,5,7-trisubstituted Benzimidazole Derivatives

In its first aspect the present invention provides compound of formulaI:

or an N-oxide thereof, or any of its isomers or any mixture of itsisomers, or a pharmaceutically acceptable salt thereof,wherein

-   R⁵ is halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl,    alkoxy, -alkyl-OR^(a), —CH═N—O—R^(a) or —(C═O)—O-alkyl;-    wherein R^(a) is hydrogen or alkyl;-    wherein one of R^(b) and R^(c) is hydrogen; and-    the other of R^(b) and R^(c) is    -   hydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl,        trifluoromethoxy, alkyl, alkoxy, alkylcarbonyl or        —NR^(d)—(C═O)—R^(e);        -   wherein the alkyl and alkoxy are optionally substituted with            one or more substituents selected from the group consisting            of: hydroxy, alkoxy, halo, and —NR′R″;        -   R^(d) and R^(e) independently of each other are selected            from hydrogen and alkyl;        -   R′ and R″ independently of each other are selected from            hydrogen and alkyl;    -   —NR^(f)R^(g), -alkyl-NR^(f)R^(g), —(C═O)—NR^(f)R^(g),        —O-NR^(f)R^(g); —NR_(h)-alkyl-NR^(f)R^(g);        -   wherein R^(h) is hydrogen or alkyl;        -   R^(f) and R^(g) independently of each other are hydrogen or            alkyl; or        -   R^(f) and R^(g) together with the nitrogen to which they are            attached form a 5- to 7-membered heterocyclic ring,            which heterocyclic ring may optionally comprise as a ring            member, one oxygen atom, and/or one additional nitrogen            atom, and/or one carbon-carbon double bond, and/or one            carbon-nitrogen bond; and            -   which heterocyclic ring may optionally be substituted                with trifluoromethyl, alkyl, hydroxyalkyl, or —NR′R″;            -   wherein R′ and R″ independently of each other are                hydrogen or alkyl;-    or R^(b) and R^(c) together represent —O—CH₂—O—;-   or R⁷ is    -   —NR^(h)—(C═O)—R^(l), —N═CH—R^(l), or —C≡C—R^(l);        -   wherein R^(h) is hydrogen or alkyl; and        -   R^(l) is alkyl or phenyl, which alkyl or phenyl is            optionally substituted with hydroxy, trifluoromethyl, cyano            or alkyl; or    -   —NR^(j)R^(k), -alkyl-NR^(j)R^(k), —CH═CH—(C═O)—NR^(j)R^(k),        —CH═CH—(C═O)—O-alkyl, -alkyl-(C═O)—NR^(j)R^(k), or        —C≡C—CH²NR^(j)R^(k);        -   wherein R′ and R″ independently of each other are selected            from the group consisting of hydrogen, alkyl, -alkyl-CN,            -alkyl-R′R″ and -alkyl-R^(l);            -   wherein R′ and R″ independently of each other are                hydrogen or alkyl;            -   R^(l) is a 5- to 7-membered heterocyclic ring comprising                one nitrogen atom,                -   which heterocyclic ring may optionally comprise as a                    ring member, one oxygen atom, and/or one additional                    nitrogen atom, and/or one carbon-carbon double bond,                    and/or one carbon-nitrogen bond; and                -   which heterocyclic ring may optionally be                    substituted with trifluoromethyl, alkyl,                    hydroxyalkyl, or —NR′R″;                -    wherein R′ and R″ independently of each other are                    hydrogen or alkyl;        -   or R^(j) and R^(k) together with the nitrogen to which they            are attached form a 5- to 7-membered heterocyclic ring,            -   which heterocyclic ring may optionally comprise as a                ring member, one oxygen atom, and/or one additional                nitrogen atom, and/or one carbon-carbon double bond,                and/or one carbon-nitrogen bond; and            -   which heterocyclic ring may optionally be substituted                with trifluoromethyl, alkyl, hydroxy, hydroxyalkyl, or                —NR′R″;                -    wherein R′ and R″ independently of each other are                    hydrogen or alkyl;-   or R⁷ is a heteroaryl group    -   which heteroaryl group is optionally substituted with one or        more substituents independently selected from the group        consisting of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, nitro,            alkyl, or alkoxy;-   with the proviso that the compound is not-   7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,-   7-(3-Pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole,-   1,7-Diphenyl-5-trifluoromethylbenzimidazole,-   7-benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole, or-   7-amino-1-phenyl-5-trifluoromethylbenzimidazole.

In one embodiment, R⁵ is halo. In a further embodiment, R⁵ istrifluoromethyl. In a still further embodiment, R⁵ is trifluoromethoxy.In a further embodiment, R⁵ is cyano. In a still further embodiment, R⁵is nitro. In a further embodiment, R⁵ is alkyl such as methyl, ethyl ortertbutyl. In a still further embodiment, R⁵ is alkoxy. In a furtherembodiment, R⁵ is -alkyl-OR^(a). In a still further embodiment, R⁵ is—CH═N—O—R^(a), such as —CH═N—OH or —CH═N—O—CH₃. In a further embodiment,R⁵ is —(C═O)—O-alkyl, such as ethoxycarbonyl. In a still furtherembodiment, R^(a) is hydrogen. In a further embodiment, R^(a) is alkyl.In a further embodiment, R⁵ is hydroxyalkyl, such as hydroxymethyl.

In a special embodiment, R⁵ is selected from the group of methyl,tertbutyl, trifluoromethyl, hydroxymethyl, cyano, ethoxycarbonyl,—CH═N—OH and —CH═N—O—CH₃.

In a further embodiment, R⁷ is

wherein one of R^(b) and R^(c) is hydrogen; and

the other of R^(b) and R^(c) is

-   -   hydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl,        trifluoromethoxy, alkyl, alkoxy, alkylcarbonyl or        —NR^(d)—(C═O)—R^(e);        -   wherein the alkyl and alkoxy are optionally substituted with            one or more substituents selected from the group consisting            of: hydroxy, alkoxy, halo, and —NR′R″;        -   R^(d) and R^(e) independently of each other are selected            from hydrogen and alkyl;        -   R′ and R″ independently of each other are selected from            hydrogen and alkyl;    -   —NR^(f)R^(g), -alkyl-NR^(f)R^(g), —(C═O)—NR^(f)R^(g),        —O—NR^(f)R^(g); —O-alkyl-NR^(f)R^(g); —NR^(h)-alkyl-NR^(f)R_(g);        -   wherein R^(h) is hydrogen or alkyl;        -   R^(f) and R^(g) independently of each other are hydrogen or            alkyl; or        -   R^(f) and R^(g) together with the nitrogen to which they are            attached form a 5- to 7-membered heterocyclic ring,            -   which heterocyclic ring may optionally comprise as a                ring member, one oxygen atom, and/or one additional                nitrogen atom, and/or one carbon-carbon double bond,                and/or one carbon-nitrogen bond; and            -   which heterocyclic ring may optionally be substituted                with trifluoromethyl, alkyl, hydroxyalkyl, or —NR′R″;                -   wherein R′ and R″ independently of each other are                    hydrogen or alkyl.

In a further embodiment, R^(b) is hydrogen. In a still furtherembodiment, R^(c) is hydrogen.

In a further special embodiment, the other of R^(b) and R^(c) ishydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl,trifluoromethoxy, alkyl, alkoxy, alkylcarbonyl or —NR^(d)—(C═O)—R^(e);wherein the alkyl and alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of: hydroxy, halo, and—NR′R″; and R^(d), R^(e), R′ and R″ are as defined above.

In a still further embodiment, the other of R^(b) and R^(c) is hydrogen.In a further embodiment, the other of R^(b) and R^(c) is halo, such aschloro or fluoro. In a still further embodiment, the other of R^(b) andR^(c) is cyano. In a further embodiment, the other of R^(b) and R^(c) ishydroxy. In a still further embodiment, the other of R^(b) and R^(c) isnitro. In a further embodiment, the other of R^(b) and R^(c) istrifluoromethyl. In a still further embodiment, the other of R^(b) andR^(c) is trifluoromethoxy. In a further embodiment, the other of R^(b)and R^(e) is optionally substituted alkyl, such as alkyl, hydroxyalkylor haloalkyl. In a special embodiment, the other of R^(b) and R^(c) ishydroxymethyl, 1-hydroxyethyl or 2-hydroxy-2-propyl. In a furtherembodiment, the other of R^(b) and R^(c) is alkoxy, such as methoxy. Ina still further embodiment, the other of R^(b) and R^(c) is alkyl oralkoxy substituted with —NR′R″. In a special embodiment, the other ofR^(b) and R^(c) is aminomethyl, dimethylaminomethyl, diethylaminomethylor dimethylaminoethoxy. In a further embodiment, the other of R^(b) andR^(c) is alkylcarbonyl, such as acetyl. In a further embodiment, theother of R^(b) and R^(c) is —NR^(d)—(C═O)—R^(e), such as acetamido orN-methyl-acetamido. In a still further embodiment, R^(d) is hydrogen. Ina further embodiment, R^(d) is alkyl, such as methyl. In a still furtherembodiment, R^(e) is alkyl, such as methyl.

In a still further embodiment, the other of R^(b) and R^(c) is—NR^(f)R^(g). In a further embodiment, the other of R^(b) and R^(c) is-alkyl-NR^(f)R^(g). In a still further embodiment, the other of R^(b)and R^(c) is —(C═O)-NR^(f)R_(g), such as aminocarbonyl. In a furtherembodiment, the other of R^(b) and R^(c) is —O—NR^(f)R^(g). In a stillfurther embodiment, the other of R^(b) and R^(c) is—O-alkyl-NR^(f)R^(g). In a further embodiment, the other of R^(b) andR^(c) is —NR^(h)-alkyl-N^(f)R^(g). In a special embodiment, the other ofR^(b) and R^(c) is amino, dimethylamino, methylamino or ethylamino. In afurther special embodiment, the other of R^(b) and R^(c) is1,2,3,6-tetrahydropyridin-1-ylmethyl, 1-methylpiperazin4-yl-methyl,morpholin-4-yl-methyl or 2-(morpholin-4-yl)ethoxy.

In a further embodiment, R^(b) and R^(c) together represent —O—CH₂—O—.Thus, R⁷ is 3,4-methylenedioxyphenyl.

In a still further embodiment, R⁷ is

-   -   —NR^(h)—(C═O)—R^(l), —N═CH—R^(l), or —C≡C—R^(l);    -    wherein R^(h) is hydrogen or alkyl; and    -    R^(i) is alkyl or phenyl, which alkyl or phenyl is optionally        substituted with hydroxy, trifluoromethyl, cyano or alkyl; or    -   —NR^(j)R^(k), -alkyl-NR^(j)R^(k), —CH═CH—(C═O)—NR^(j)R^(k),        —CH═CH—(C═O)—O-alkyl, -alkyl-(C═O)—NR^(j)R^(k), or        —C≡CH₂—NR^(j)R^(k);        -   wherein R^(j) and R^(k) independently of each other are            selected from the group consisting of hydrogen, alkyl,            -alkyl-CN, -alkyl-R′R″ and -alkyl-R^(l);            -   wherein R′ and R″ independently of each other are                hydrogen or alkyl;            -   R^(l) is a 5- to 7-membered heterocyclic ring comprising                one nitrogen atom,                -   which heterocyclic ring may optionally comprise as a                    ring member, one oxygen atom, and/or one additional                    nitrogen atom, and/or one carbon-carbon double bond,                    and/or one carbon-nitrogen bond; and which                    heterocyclic ring may optionally be substituted with                    trifluoromethyl, alkyl, hydroxyalkyl, or —NR′R″;                -    wherein R′ and R″ independently of each other are                    hydrogen or alkyl;        -   or R^(j) and R^(k) together with the nitrogen to which they            are attached form        -   a 5- to 7-membered heterocyclic ring,            -   which heterocyclic ring may optionally comprise as a                ring member, one oxygen atom, and/or one additional                nitrogen atom, and/or one carbon-carbon double bond,                and/or one carbon-nitrogen bond; and            -   which heterocyclic ring may optionally be substituted                with trifluoromethyl, alkyl, hydroxy, hydroxyalkyl, or                —NR′R″;                -   wherein R′ and R″ independently of each other are                    hydrogen or alkyl.

In a further embodiment, R⁷ is —NR^(h)—(C═O)—R^(l), such as acetamido.

In a still further embodiment, R⁷ is —N═CH—R^(l), such asbenzylideneamino, 4-cyanobenzylideneamino or 3-cyanobenzylideneamino.

In a further embodiment, R⁷ is or —C≡CH—R^(l), such as4-hydroxy-butyn-1-yl.

In a still further embodiment, R⁷ is —NR^(j)R^(k), such as4-morpholinyl, N-methyl-N-(4-hydroxyethylpiperazin-1-yl-ethyl)-amino,N-methyl-N-(4-methylpiperazin-1-yl-ethyl)-amino or3-dimethylamino-pyrrolidin-1-yl.

In a further embodiment, R⁷ is -alkyl-NR^(j)R^(k), such asdiethylaminopropyl or N-methyl-N-(cyanoethyl)-aminobutyl.

In a still further embodiment, R⁷ is —CH═CH—(C═O)—NR^(j)R^(k), such as3-(diethylamino)-propen-3-one-1-yl,3-(4-methylpiperazin-1-yl)-propen-3-one-1-yl,3-(piperidin-1-yl)-propen-3-one-1-yl,3-(morpholin-4-yl)-propen-3-one-1-yl,3-(homopiperazin-4-yl)-propen-3-one-1-yl,3-(cyanoethylamino)-propen-3-one-1-yl,3-(propylamino)-propen-3-one-1-yl,3-(dimethylaminoethylamino)-propen-3-one-1-yl,3-(4-trifluoromethyl-piperidin-1-yl)-propen-3-one-1-yl,3-(pyrrolidin-1-yl)-propen-3-one-1-yl,3-(2,5-dihydropyrrol-1-yl)-propen-3-one-1-yl,N-ethyl-N-isopropyl-carbamoyl-ethenyl,1-methylpiperidineyl-methyl-carbamoyl-ethenyl,N-methyl-N-(1-methylpyrrolidin-3-yl)-carbamoyl-ethenyl,N-methyl-N-(1-methylpiperidine-4-yl)-carbamoyl-ethenyl orN-methyl-N-(cyanoethyl)-carbamoyl-ethenyl.

In a still further embodiment, R⁷ is —CH═CH—(C═O)—O-alkyl, such asacetonylidenemethyl.

In a further embodiment, R⁷ is -alkyl-(C═O)—NR^(j)R^(k), such asN,N-diethylcarbamoylethyl.

In a still further embodiment, R⁷ is —C≡C—CH₂—NR^(j)R^(k), such as3-(morpholin-4-yl)-propyn-1-yl, 3-(piperidin-1-yl)-propyn-1-yl or3-(1-(1,2,3,6-tetrahydropyridinyl))propyn-1-yl.

In a further embodiment, R⁷ is a heteroaryl group which heteroaryl groupis optionally substituted with one or more substituents independentlyselected from the group consisting of: halo, trifluoromethyl,trifluoromethoxy, cyano, nitro, alkyl, and alkoxy.

In a still further embodiment, R⁷ is indolyl, pyridyl or furyloptionally substituted halo or methyl. In a special embodiment, R⁷ isselected from 1-Methyl-5-indolyl, pyridin4-yl, pyridin-3-yl or3-chloro-pyridin-4-yl.

In a special embodiment the chemical compound of the invention is

-   7-(3-Chlorophenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime;-   O-Methyl 7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime;-   7-(N-benzylideneamino)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(N-(4-cyanobenzylidene)amino)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(N-(3cyanobenzylidene)amino)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Aminophenyl)-5-cyano-1-phenylbenzimidazole;-   7-(3-(Hydroxymethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   1-Phenyl-7-(3-(1,2,3,6-tetrahydropyridine-1-ylmethyl)phenyl)-5-trifluoromethyl-benzimidazole;-   7-(3-Acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole;-   7-(3-Aminophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole;-   5-(Ethoxycarbonyl)-7-(3-(hydroxymethyl)phenyl)-1-phenylbenzimidazole;-   7-(3-Cyanophenyl)-1-phenyl-5-trifluorophenylbenzimidazole;-   5-Cyano-7-(3-nitrophenyl)-1-phenylbenzimidazole;-   5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole;-   5-Cyano-7-(3-((1-methylpiperazin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;-   5-Cyano-7-(3-(diethylaminomethyl)phenyl)-1-phenylbenzimidazole;-   7-(3-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole;-   5-Cyano-7-(4-methoxyphenyl)-1-phenylbenzimidazole;-   5-Cyano-7-(3-methoxyphenyl)-1-phenylbenzimidazole;-   5-Cyano-7-(4-cyanophenyl-1-phenylbenzimidazole;-   5-Cyano-7-(3-fluorophenylyl -phenylbenzimidazole;-   5-Cyano-7-(4-hydroxyphenyl)-1-phenylbenzimidazole;-   5-Cyano-7-[3-(dimethylamino)phenyl]-1-phenylbenzimidazole;-   5-Cyano-7-(3,4-methylenedioxyphenyl)-1-phenyl benzimidazole;-   5-Cyano-7-(pyridinyl)-1-phenylbenzimidazole;-   7-(3-Aminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;-   5-Ethoxycarbonyl-7-(3-((morpholin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;-   5-Ethoxycarbonyl-7-(3-((1-methylpiperazin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;-   5-Ethoxycarbonyl-7-(3-((dimethylamino)methyl)phenyl)-1-phenylbenzimidazole;-   5-Cyano-7-3-cyanophenylyl -phenylbenzimidazole;-   5-Cyano-7-(4-nitrophenyl)-1-phenylbenzimidazole;-   7-(4-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole;-   7-(3-Acetamidophenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   0-Methyl 7-(3-acetmidophenyl)-5-formyl-1-phenylbenzimidazole oxime;-   0-Methyl 7-(3(dimethylamino)phenyl)-5-formyl-1-phenylbenzimidazole    oxime;-   5-Cyano-7-(4-diethylaminomethylphenyl)-1-phenylbenzimidazole;-   7-(4-Benzamidyl)-5-cyano-1-phenylbenzimidazole;-   7-(3-Acetamidophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;-   7-(3-Ethylaminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;-   7-(3-Dimethylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole;-   7-(3-Methylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole;-   1-Phenyl-7-(3((4-methylpiperazin-1-yl)methyl)phenyl)-5-trifluoromethylbenzimidazole;-   7-(3-(1-Morpholinylmethyl)phenyl)-1-phenyl-5-trifluoramethylbenzimidazole;-   7-(3-((Dimethylamino)methyl)phenyl)-1-phenyl    -5-trifluoromethylbenzimidazole;-   5-Cyano-7-(4-(2-(4-morpholino)ethoxy)phenyl)-1-phenylbenzimidazole;-   7-(3-(N-Methyl    acetamido)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   1-Phenyl-7-(4-pyridyl)-5-trifluoromethylbenzimidazole;-   5-(Hydroxymethyl)-1-phenyl-7-(3-trifluoromethoxyphenyl)benzimidazole;-   7-(4-pyridyl N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3chloro-4-pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-chloro-4-pyridyl-N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Fluorophenyl)-1-phenyl-5-trifluorophenylbenzimidazole;-   3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid    methyl ester;-   3-(6-Cyano-3-phenyl-3H-benzimidazol-4-yl)acrylic acid methyl ester;-   7-(4-Morpholinyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   5-t-Butyl-7-(3-dimethylaminophenyl)-1-phenylbenzimidazole;-   7-(3-(1-Methoxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(1-Methyl-5-indolyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-(1-Hydroxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Furyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   N,N-Diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;-   1-(4-Methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3-H-benzimidazol-4-yl)prop-2-en-1-one;-   3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-piperidinylprop-2-en-1-one;-   1-(4-Morpholinyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;-   1-(4-Methyl-[1,4]-hexahydrodiazepin-1-yl)-3-(3-phenyl-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;-   N-(2-Cyanoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;-   3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-N-propylacrylamide;-   N-(2-Dimethylaminoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;-   3-(3-Phenyl-trifluoromethyl-3H-benzimidazol-4-yl)-1-(4-trifluoromethyl-piperidin-1-yl)prop-2-en-1-one;-   7-(3-(2-Hydroxy-2-propyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(4-Hydroxypiperidinyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(3-Fluorophenyl)-5-methyl-1-phenylbenzimidazole;-   7-(4-Hydroxybut-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   7-(1-(1-(4-Hydroxyethylpiperazinyl)ethyl)-1-methylamino)-1-phenyl-5-trifluoromethyl-benzimidazole;-   7-(1-(1-(4-Methylpiperazinyl)ethyl)-1-methyl)amino-I    -phenyl-5-trifluoromethyl-benzimidazole;-   7-(3-(4-Morpholino)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole;-   N,N-Diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)propionamide;-   3(6-tert-Butyl-3-phenyl-3H-benzimidazol-4-yl)-1-(piperidin-1-yl)prop-2-en-1-one;-   N-Ethyl-N-isopropyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl    )acrylamide;-   N-(1-Methylpipeddin-4-yl)methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-yl)-acrylamide;    N-Methyl-N-(-methylpyrrolidin-3-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;-   3(6-tert-Butyl-3-phenyl-3H-benzimidazolyl)-N-methyl-N-(1-methylpiperidin-4-yl)-acrylamide;-   7-(4-(Diethylamino)-butyl)-phenyl-5-trifluoromethylbenzimidazole;-   7-(4-((N-(2-Cyanoethyl)-N-methyl)amino)-1-butyl)-1-phenyl-5-trifluoromethyl-benzimidazole;-   3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol4-yl)-1-(pyrollidin-1-yl)prop-2-en-1-one;-   1-(2,5-Dihydropyrrol-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;-   N-(2-Cyanoethyl)-N-methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazolyl)-acrylamide;-   1-Phenyl-7-(3-(1-(1,2,3,6-tetrahydropyridinyl))prop-1-ynyl)-5-trifluoromethylbenzimidazole;-   1-Phenyl-7-(3-(1-piperidinyl)prop-1-ynyl-5-trifluoromethylbenzimidazole;-   7-[1-(3-Dimethylamino)pyrrolidinyl]-1-phenyl-5-trifluoromethylbenzimidazole;-   or an N-oxide thereof, or any of its isomers or any mixture of its    isomers, or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In one embodiment alkyl represents a C₁₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother embodiment of this invention alkyl represents a C₁₋₃-alkylgroup, which may in particular be methyl, ethyl, propyl or isopropyl.

In the context of this invention an alkoxy group designates an“alkyl-O-” group, wherein alkyl is as defined above.

5- to 7-membered heterocyclic rings comprising one nitrogen atom includefor example, but not limited to, pyrolidine, piperidine, homopiperidine,pyrroline, tetrahydropyridine, pyrazolidine, imidazolidine, piperazine,homopiperazine, and morpholine.

In the context of this invention a heteroaryl group designates anaromatic mono- or bicyclic heterocyclic group, which holds one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic5- and 6 membered heterocyclic monocyclic groups, including for example,but not limited to, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol4-yl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-pyrimidyl or 6-pyrimidyl.

Preferred bicyclic heteroaryl groups of the invention includeindolizinyl, in particular 2-, 5- or 6-indolizinyl; indolyl, inparticular 2-, 5- or 6-indolyl; isoindolyl, in particular 2-, 5- or6-isoindolyl; benzo[b]furanyl, in particular 2-, 5- or 6-benzofuranyl;benzo[b]thienyl, in particular 2-, 5- or 6-benzothienyl; benzimidazolyl,in particular 2-, 5- or 6-benzimidazolyl; benzothiazolyl, in particular5- or 6-benzothiazolyl; purinyl, in particular 2- or 8-purinyl;quinolinyl, in particular 2-, 3-, 6- or 7-quinolinyl; isoquinolinyl, inparticular 3-, 6- or 7-isoquinolinyl; cinnolinyl, in particular 6- or7-cinnolinyl; phthalazinyl, in particular 6- or 7-phthalazinyl;quinazolinyl, in particular 2-, 6- or 7-quinazolinyl; quinoxalinyl, inparticular 2- or 6-quinoxalinyl; 1,8-naphthyridinyl, in particular1,8-naphthyridin-2-, 3-, 6- or 7-yl; pteridinyl, in particular 2-, 6- or7-pteridinyl; and indenyl, in particular 1-, 2-, 3-, 5- or 5-indenyl.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate derived, the phthalate,the salicylate, the sorbate, the stearate, the succinate, the tartrate,the toluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Metal salts of a chemical compound of the invention include alkali metalsalts such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention include compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may contain one or more chiral centres and thatsuch compounds exist in the form of isomers.

The racemates of these isomers and the individual isomers themselves arewithin the scope of the present invention.

Methods for the resolution of optical isomers, known to those skilled inthe art may be used, and will be apparent to the average worker skilledin the art. Such methods include those discussed by J. Jaques, A.Collet, and S. Wilen in “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

N-oxides

In the context of this invention an N-oxide designates an oxidederivative of a nitrogen containing compound, e.g. N-containingheterocyclic compounds capable of forming such N-oxides, and compoundsholding one or more amino groups. For example, the N-oxide of a compoundcontaining a pyridyl may be the 1-oxy-pyridin-2,-3 or -4-yl derivative.

N-oxides of the compounds of the invention may be prepared by oxidationof the corresponding nitrogen base using a conventional oxidizing agentsuch as hydrogen peroxide in the presence of an acid such as acetic acidat an elevated temperature, or by reaction with a peracid such asperacetic acid in a suitable solvent, e.g. dichloromethane, ethylacetate or methyl acetate, or in chloroform or dichloromethane with3-chloroperoxybenzoic acid.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention “label” stands for thebinding of a marker to the compound of interest that will allow easyquantitative detection of said compound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradionuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ²⁵¹I, ²³¹I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

The compounds of this invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of this invention.

Biological Activity

Compounds of the invention are capable of modulating the GABA_(A)receptor complex. They may be tested for their ability to bind to theGABA_(A) receptor complex, including specific subunits thereof.

The compounds of the present invention, being ligands for GABA_(A)receptors, are therefore of use in the treatment and/or prevention of avariety of disorders of the central nervous system. Thus in furtheraspect, the compounds of the invention are considered useful for thetreatment, prevention or alleviation of a disease, disorder or conditionresponsive to modulation of the GABA_(A) receptor complex in the centralnervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of

-   -   anxiety disorders, such as panic disorder with or without        agoraphobia, agoraphobia without history of panic disorder,        animal and other phobias including social phobias,        obsessive-compulsive disorder, and generalized or        substance-induced anxiety disorder;    -   stress disorders including post-traumatic and acute stress        disorder;    -   sleep disorders;    -   memory disorder;    -   convulsive disorders, for example epilepsy, or febrile        convulsions in children;    -   premenstrual syndrome;    -   muscle spasm or spasticity, e.g. in paraplegic patients;    -   the effects of substance abuse or dependency, including alcohol        withdrawal; and    -   disorders of circadian rhythm, e.g. in subjects suffering from        the effects of jet lag or shift work.

The compounds of the invention may also be useful for:

-   -   inducing and maintaining anaesthesia, sedation and muscle        relaxation; and    -   pre-medication prior to anaesthesia or minor procedures such as        endoscopy, including gastric endoscopy;

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Further, the compounds of the invention may be useful as radioligands inassays for detecting compounds capable of binding to the human GABA_(A)receptor.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the invention.

While a compound of the invention for use in therapy may be administeredin the form of the raw chemical compound, it is preferred to introducethe active ingredient, optionally in the form of a physiologicallyacceptable salt, in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefore, and,optionally, other therapeutic and/or prophylactic ingredients, known andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or with-out carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilizaton from solution, for constitution with asuitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

The pharmaceutical composition of the invention can be manufactured byany skilled person by use of standard methods and conventionaltechniques appropriate to the desired formulation. When desired,compositions adapted to give sustained release of the active ingredientmay be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms-or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

EXAMPLES

The invention is further illustrated with reference to the followingexamples which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.2 g, 8.2mmol), 3-aminophenyl boronic acid (1.68 g, 12.3 mmol), sodium carbonate(5.68 g, 41 mmol), 1,3-propanediol (2.94 ml, 41 mmol) andbis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in amixture of water (13 ml) and dimethoxyethane (26 ml) was stirred atreflux overnight The cooled reaction mixture was partitioned betweenethyl acetate and water, and the organic extract was purified by columnchromatography on silica gel eluting with a mixture of dichloromethaneand methanol (99:1, v/v). The product was isolated by removal of solventfrom appropriate eluate fractions followed by crystallisation of theresidue from 2-propanol (50 ml). Yield: 2.7 g (93%), m/z, 354.1 (M+H)⁺.

Example 2 1-Phenyl-7-(3-pyridyl)-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1mmol), diethyl 3-pyridylborane (220 mg, 1.5 mmol), sodium bicarbonate(420 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg,0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) wasstirred at reflux overnight The cooled reaction mixture was partitionedbetween ethyl acetate and water, and the organic extract was purified bycolumn chromatography on silica gel eluting with a mixture ofdichloromethane and acetone (9:1, v/v). The product was isolated byremoval of solvent from appropriate eluate fractions followed bytrituration of the residue with a mixture of water and ethanol. Yield:130 mg (38%), m/z, 340.1 (M+H)⁺.

Example 3 1.7-Diphenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1mmol), benzeneboronic acid (180 mg, 1.5 mmol), potassium carbonate (700mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) wasstirred at reflux overnight. The cooled mixture was partitioned betweenwater and ethyl acetate. The organic phase was collected, washed withbrine, dried and concentrated under reduced pressure. Recrystallisationfrom methanol afforded the product as an off-white solid (160 mg, 47%),m/z, 339.1 (M+H)⁺.

Example 4 7-Benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (300 mg, 1mmol), benzoylchloride (0.23 ml, 2 mmol) and triethyl amine (0.3 ml, 2mmol) in tetrahydrofurane (10 ml) was stirred at ambient temperatureovernight. The solvent was removed under reduced pressure and theresidue was partitioned between ethyl acetate and hydro chloric acid (4M). The aqueous phase was rendered alkaline with saturated, aqueoussodium carbonate and extracted with ethyl acetate. The extract was driedand concentrated under reduced pressure and the resultant gum wastriturated with a mixture of diethyl ether and petroleum ether to leavethe solid, off-white product (145 mg, 38%), m/z, 382.1 (M+H)⁺.

Example 5 7-(3-Chlorophenyl)-1-Phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 2.6mmol), 3-chlorobenzeneboronic acid (0.6 g, 3.87 mmol), 1,3-propanediol(1 ml, 12.9 mmol), potassium carbonate (1.8 g, 12.9 mmol) andbis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) wasstirred at reflux for one hour. The cooled mixture was partitionedbetween water and ethyl acetate. The organic extract was dried andconcentrated under reduced pressure. The concentrate was purified bychromatography on silica gel eluting with a mixture of ethyl acetate andligroin (2:3, v/v). Removal of solvent left the desired product as awhite solid (0.9 g, 94%) m/z, 373.1 (M+H)⁺.

Example 6 7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime

To a solution of 7-(3-aminophenyl)-5-cyano-1-phenylbenzimidazole (3.4 g,11.0 mmol) in a mixture of formic acid (70 ml ) and water (23 ml),saturated with nitrogen, was added Raney nickel (3 g) and the resultantmixture was stirred at reflux for 1 hour. The hot reaction mixture wasfiltered through a pad of celite, which was washed with water. Thefiltrate was concentrated under reduced pressure and the concentrate waspartitioned between saturated, aqueous sodium carbonate and ethylacetate. The organic phase was purified by column chromatography onsilica gel eluting with a mixture of ethyl acetate and methanol (9:1v/v) to yield 7-(3-(formylamino)phenyl)-5-formyl-1-phenylbenzimidazoleas a yellowish solid (1 g, 27%).

The above intermediate (0.4 g, 1.17 mmol) was suspended in abs. ethanol(10 ml) and hydroxylamine hydrochloride (0.12 g, 1.76 mmol) was added.The resultant mixture was stirred at reflux for 1 hour. The crudeproduct, which precipitated upon cooling, was filtered off and washedsuccessively with aqueous sodium carbonate, water and ethanol. Columnchromatography on silica gel eluting with ethyl acetate left the titleproduct as white crystals (50 mg, 13%) m/z, 329.1 (M+H)⁺.

Example 7 O-Methyl 7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazoleoxime

This was prepared analogously to the above product from7-(3-(formylamino)phenyl)-5-formyl-1-phenylbenzimidazole (0.4 g, 1.17mmol) and O-methyl hydroxylamine hydrochloride (0.15 g, 1.76 mmol). Theproduct was obtained as a white solid (0.3 g, 74%) m/z, 343.2 (M+H)⁺.

Example 8 7-(N-benzylideneamino)-1-phenyl-5-trifluoromethylbenzimidazole

To a solution of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (0.50g, 1.81 mmol) in anhydrous toluene (10 ml) was added benzaldehyde,p-toluenesulphonic acid (10 mg) and molecular sieves. The resultantmixture was stirred at reflux for 1.5 hours. The molecular sieves wereremoved by filtration and the filtrate was concentrated under reducedpressure. The concentrate was partitioned between aqueous sodiumcarbonate (2 M) and ethyl acetate. The organic phase was dried andconcentrated, and the concentrate was eluted through silica gel with amixture of ethyl acetate and ligroin (1:1 v/v). Removal of solvent fromthe eluate left the desired product as a yellow solid (0.37 g, 56%) m/z,366.1 (M+H)⁺.

Example 9 7-(N-(4cyanobenzylidene)amino-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogously to the above product from7-amino-1-phenyl-5-trifluoromethylbenzimidazole (1.09, 3.61 mmol) and4-cyanobenzaldehyde (0.47 g, 3.61 mmol) yielding 0.96 g (68%) m/z, 391.1(M+H)⁺.

Example 107-(N-(3-cyanobenzylidene)amino)-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogously to the above product from7-amino-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 3.61 mmol) and3-cyanobenzaldehyde (0.47 g, 3.61 mmol) yielding 0.90 g (64%) m/z, 391.1(M+H)⁺.

Example 11 7-(3-Aminophenyl)-5-cyano-1-Phenylbenzimidazole

A mixture of 5-cyano-7-iodo-1-phenylbenzimidazole (1.9 g, 5.5 mmol),3-aminophenylboronic acid hemisulphate (1.53 g, 8.3 mmol),1,3-propanediol (2 ml, 27.5 mmol), potassium carbonate (3.8 g, 27.5mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol)in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred atreflux for 1 hour. The resultant mixture was poured into water and thecrude product was filtered off, washed with water and air-dried.Trituration in dichloromethane offered the desired product as a greyishsolid (1.5 g, 88%) m/z, 311.1 (M+H)⁺.

Example 127-(3-(Hydroxymethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 5-cyano-7-iodo-1-phenylbenzimidazole (1.0 g, 2.7 mmol),3-(hydroxymethyl)phenylboronic acid (0.62 g, 4.1 mmol), 1,3-propanediol(0.97 ml, 13.5 mmol), potassium carbonate (1.87 g, 13.5 mmol) andbis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in amixture of dimethoxyethane (10 ml) and water (5 ml) was stirred atreflux for 1 hour. The cooled reaction mixture was concentrated underreduced pressure, and the concentrate was partitioned between water andethyl acetate. The organic phase was dried and concentrated underreduced pressure, and the concentrate was crystallised from diethylether leaving the product as white crystals (660mg, 66%) m/z, 369.1(M+H)⁺.

Example 131-Phenyl-7-(3-(1,2,3,6-tetrahydropydridine-1-ylmethyl)phenyl)-5-trifluoromethyl-benzimidazole

A mixture of7-(3-(hydroxymethyl)phenyl-1-phenyl-5-trifluoromethylbenzimidazole (0.55g, 1.5 mmol), pyridine (1 ml) and p-toluenesulphonyl chloride (0.57 g, 3mmol) was stirred at gentle reflux overnight. Ethyl acetate (5 ml) wasadded to the cooled mixture and the resultant precipitate was filteredoff, washed with ethyl acetate and air-dried. This intermediatepyridinium sulphonate (1 g) was dissolved in dimethyl formamide (10 ml).Sodium borohydride (0.23 g, 6 mmol) was added and the resultant mixturewas stirred at ambient temperature overnight. Aqueous calcium chloride(2 M, 30 ml) was added carefully, and the resultant mixture wasextracted with ethyl acetate. The organic extract was washed with brine,dried over magnesium sulphate and concentrated under reduced pressure.The residue was purified on silica gel eluting with ethyl acetate.Removal of solvent from the eluate and crystallisation from 2-propanolafforded the desired product (15 mg, 2%) m/z, 434.2 (M+H)⁺.

Example 14 7-(3-Acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole

A mixture of 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (0.70 g, 1.8mmol), 3-acetamidophenylboronic acid (0.48 g, 2.7 mmol), 1,3-propanediol(0.65 ml, 8.9 mmol), potassium carbonate (1.23 g, 8.9 mmol) andbis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in amixture of dimethoxyethane (10 ml) and water (5 ml) was stirred atreflux for 1 hour. The cooled reaction mixture was concentrated underreduced pressure, and the concentrate was partitioned between water andethyl acetate. The organic phase was dried and concentrated underreduced pressure, and the concentrate was triturated in ethyl acetateleaving the product as an off-white solid (0.48 g, 67%) m/z, 400.2(M+H)⁺.

Example 15 7-(3-Aminophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole

This was prepared analogously to the above product from5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (2.1 g, 5.36 mmol),3-aminophenylboronic acid (1.1 g, 8.04 mmol), 1,3-propanediol (1.9 ml,26.8 mmol), potassium carbonate (3.7 g, 26.8 mmol) andbis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in amixture of dimethoxyethane (10 ml) and water (5 ml). The title productwas obtained as an off-white solid (1.30 g, 68%) m/z, 358.2 (M+H)⁺.

Example 165-(Ethoxycarbonyl)-7-(3-(hydroxymethyl)phenyl)-1-phenylbenzimidazole

This was prepared analogously to7-(3-acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole from5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (2.7 g, 6.89 mmol),3-(hydroxymethyl)phenylboronic acid (1.57 g, 10.3 mmol), 1,3-propanediol(2.5 ml, 34.4 mmol), potassium carbonate (4.75 g, 34.4 mmol) andbis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) in amixture of dimethoxyethane (30 ml) and water (15 ml). The title productwas obtained as an off-white solid (2.1 g, 82%) m/z, 373.2 (M+H)⁺.

Example 17 7(3-Cyanophenyl)-1-phenyl-5-trifluorophenylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.1 g, 8mmol), 3-cyanophenylboronic acid (1.76 g, 12 mmol), 1,3-propanediol (2.9ml, 40 mmol), potassium carbonate (5.54 g, 40 mmol) andbis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in amixture of dimethoxyethane (30 ml) and water (15 ml) was stirred atreflux for 4 hours. The cooled reaction mixture was concentrated underreduced pressure, and the concentrate was partitioned between water andethyl acetate. The organic phase was dried and concentrated underreduced pressure, and the concentrate was purified by columnchromatography on silica gel eluting with a mixture of ligroin and ethylacetate (1:1 v/v). The product was isolated by evaporation of solventfrom the eluate, and crystallised by trituration with diethyl ether(0.78 g, 27%) m/z, 364.1 (M+H)⁺.

Example 18 5-Cyano-7-(3-nitrophenyl)-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 3-nitrophenylboronic acid (84 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (13 mg, 8%) m/z, 341.0(M+H)⁺.

Example 19 5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazoletrifluoracetic acid salt

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),3-hydroxymethylphenyl-boronic acid (76 mg, 0.5 mmol), ethanol (3.0 ml)and potassium carbonate (2 M in water, 0.5 ml, 138 mg, 1.0 mmol) wereadded sequentially to a tube under nitrogen and refluxed for 22 h. Thetube was blown dry with nitrogen and the solid residue washed(trifluoroacetic acid in acetonitrile, 0.1%, 3 times 1.5 ml). The liquidwas evaporated and the resulting solid dissolved indichloromethane/methanol (19:1) and eluted through an SPE column (C18,Isolute, 2 g, 6 ml) to give a solid (190 mg). This solid was dissolvedin dimethylsulphoxide (2 ml) and eluted through a prep LCMS column togive, after removal of the solvent, the desired product as a glass (70mg, 32%) m/z, 326.3 (M+H)⁺.

Example 20

5Cyano-7-(3-((1-methylpiperazin-4yl)methyl)phenyl)-1-phenylbenzimidazoletrifluoroacetic acid salt

5-Cyano-7-iodo-1-phenylbenzimidazole (1.0 g, 2.90 mmol),3-hydroxymethyl-phenylboronic acid (440 mg, 2.90 mmol) andtetrakis(triphenylphosphine)palladium(0) (330 mg, 2.90 mmol) weredissolved in toluene (8.0 ml) and ethanol (2.0 ml). Potassium carbonate(2 M in water, 2.9 ml, 800 mg, 5.8 mmol) was added and the reactionmixture heated at reflux under a nitrogen atmosphere for 16 h. Thereaction mixture was passed through a plug of silica gel usingdichloromethane/methanol (19:1) to elute. The organic phase wasconcentrated under reduced pressure and the resultant gum trituratedwith ethyl acetate and dichloromethane.5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole was obtained asan off-white solid (500 mg, 39%) m/z, 326.2 (M+H)⁺.

5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole (500 mg, 1.54mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C.Diisopropylethylamine (0.82 ml, 4.62 mmol) and methanesulphonyl chloride(0.13 ml, 1.69 mmol) were added sequentially and the reaction mixturestirred at room temperature for 1 h. The crude solution (approximately0.14 M of product) was used directly in the next stage.

Crude 5-cyano-7-(3-methanesulphonylmethylphenyl)-1-phenylbenzimidazole(2.0 ml, 0.14 M solution in dichloromethane) was added toN-methylpiperazine (0.044 ml, 0.40 mmol) in dichloromethane (2 ml). Thereaction mixture was stirred at room temperature for 12 h then thesolvent removed under reduced pressure. Purification by prep LCMS gavethe title compound as a clear, colourless glass (43 mg, 7%) m/z, 408.6(M+H)⁺.

Example 215-Cyano-7-(3-(diethylaminomethyl)phenyl)-1-phenylbenzimidazoletrifluoroacetic acid salt

Prepared as for5-cyano-7-(3-(1-methylpiperazin-4-yl)methylphenyl)-1-phenylbenzimidazole,using 56cyano-7-(3-methanesulphonylmethylphenyl)-1-phenylbenzimidazole(2.0 ml, 0.14 M solution in dichloromethane) and diethylamine (0.041 ml,0.40 mmol) as starting materials. Purification by prep LCMS gave thetitle compound as a clear, colourless glass (43 mg, 7%) m/z, 381.4(M+H)⁺.

Example 22 7-(3-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),3-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol (3.0 ml) andpotassium carbonate (138 mg, 1.0 mmol) were combined and the mixture wasstirred at reflux overnight. The solvent was removed under reducedpressure and the crude product was purified on a 2 g silica Isolute® SPEcolumn, eluting with dichloromethane/methanol (98:2). The eluent fromthis column was evaporated under reduced pressure and the crude productwas purified further by prep LCMS, then recrystallised fromdichloromethane/diethyl ether to give the product as a white solid (64mg, 36%) m/z, 353.0 (M+H)⁺.

Example 23 5-Cyano-7-(4-methoxyphenyl)-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 4-methoxyphenylboronic acid (76 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) In a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (47 mg, 29%) m/z, 326.5(M+H)⁺.

Example 24 5-Cyano-7-(3-methoxyphenyl)-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 3-methoxyphenylboronic acid (76 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (51 mg, 31%) m/z, 326.5(M+H)⁺.

Example 25 5-Cyano-7-(4 cyanophenyl)-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 4-cyanophenylboronic acid (74 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (94 mg, 59%) m/z, 321.0(M+H)⁺.

Example 26 5Cyano-7-(3-fluorophenyl)-1-Phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 3-fluorophenylboronic acid (70 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (67 mg, 43%) m/z, 314.0(M+H)⁺.

Example 27 5-Cyano-7-(4-hydroxyphenyl)-1-phenylbenzimidazole

This was prepared in a similar manner to5-cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole, with 90 hreflux before removal of solvent using nitrogen to give an oily residue.The residue was taken up in acetonitrile (3 ml) and the resulting solidfiltered off and dried under reduced pressure to give the desiredproduct (490 mg, 77%) m/z, 312.3 (M+H)⁺.

Example 28 5-Cyano-7-[3-(dimethylamino)phenyl]-1-phenylbenzimidazole

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),3-dimethylaminophenylboronic acid (82 mg, 0.5 mmol), ethanol (3.0 ml)and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixturewas stirred at reflux overnight. The solvent was removed under reducedpressure and crude product was purified on a 2 g silica Isolute® SPEcolumn, eluting with dichloromethane/methanol (95:5). The eluent wasconcentrated under reduced pressure and the crude product was suspendedin acetonitrile then treated with diethyl ether to precipitate theproduct Recrystallisation from diethyl ether afforded the title compound(64 mg, 38%) m/z, 339.0 (M+H)⁺.

Example 29 5-Cyano-7-(3,4-methylenedioxyphenyl)-1-phenylbenzimidazole

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),3,4-methylene dioxyphenylboronic acid (83 mg, 0.5 mmol), ethanol (3.0ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and themixture was stirred at reflux overnight The solvent was removed underreduced pressure and the crude product was purified on a 2 g silicaIsolute® SPE column, eluting with dichloromethane/methanol (95:5). Theeluent was concentrated under reduced pressure and product wascrystallised from dichloromethane/diethyl ether to the title compound(75 mg, 44%) m/z, 339.8 (M+H)⁺.

Example 30 5-Cyano-7-(pyridin-4-yl)-1-phenylbenzimidazole

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),pyridin-4-yl boronic acid (62 mg, 0.5 mmol), ethanol (3.0 ml) andpotassium carbonate (138 mg, 1.0 mmol) were combined and the mixture wasstirred at reflux overnight. The solvent was removed under reducedpressure and the crude product was purified on a 2 g silica Isolute® SPEcolumn, eluting with dichloromethane/methanol (95:5). The eluent wasconcentrated under reduced pressure and the crude product was suspendedin acetonitrile then treated with diethyl ether to precipitate theproduct. The mother liquors were removed by filtration and the residualsolid was further purified on a Biotage silica gel cartridge, elutingwith dichloromethane/methanol (98:2). Recrystallisation fromdichloromethane/diethyl ether afforded the title compound (48 mg, 32%)m/z, 297.4 (M+H)⁺.

Example 31 7-(3-Aminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole

To a stirred suspension of lithium alumina hydride (0.24 g, 6.16 mmol)in anhydrous diethyl ether (20 ml) was added7-(3-aminophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole (1.1 g, 3.08mmol). Stirring was continued for 48 hours at ambient temperature in anitrogen atmosphere. Aqueous sodium bicarbonate (2 M) was added and theresultant mixture was extracted with ethyl acetate. This extract wasdried over magnesium sulphate and concentrated under reduced pressure.The concentrate was eluted through silica gel with a mixture of ethylacetate and methanol (9:1 v/v). Removal of solvent from the eluate leftthe title product as a yellow solid (0.38 g, 39%) m/z, 316.1 (M+H)⁺.

Example 325-Ethoxycarbonyl-7-(3-((morpholin-4-yl)methyl)phenyl)-1-phenylbenzimidazole

To a stirred suspension of5-ethoxycarbonyl-7-(3-(hydroxymethyl)phenyl)-1-phenylbenzimidazole (1.7g, 4.57 mmol) in anhydrous toluene (20 ml) was added thionyl chloride(0.80 ml, 10.96 mmol) and stirring was continued at ambient temperatureovernight. Excess thionyl chloride and toluene was removed byevaporation under reduced pressure. The intermediate5-ethoxycarbonyl-7-(3-(chloromethyl)phenyl)-1-phenylbenzimidazoleprecipitated from the residue upon trituration with ethyl acetate (1.56g).

This intermediate (0.5 g, 1.28 mmol) was dissolved in dimethyl formamide(5 ml) and morpholine (0.44 ml, 5.12 mmol) was added. The resultantmixture was stirred at 80° C. overnight whereupon water was added,causing a crude product to precipitate. The precipitate was filtered offand purified by column chromatography on silica gel eluting with ethylacetate. Removal of solvent from the eluate left the title product as acolourless gum. This gum was redissolved in anhydrous diethyl ether andetheral hydrochloric acid (0.5 ml, 2 M) was added to afford the desiredproduct as the HCl salt (0.40 g, 71%) m/z, 422.2 (M+H)⁺.

Example 335-Ethoxycarbonyl-7-(3-((1-methylpiperazin-4-yl)methyl)phenyl)-1-phenylbenzimidazole

This was prepared analogously to the above product from5-ethoxycarbonyl-7-(3-(chloromethyl)phenyl)-1-phenylbenzimidazole (0.50g, 1.28 mmol) and 1-methylpiperazine (0.50 g, 3.84 mmol) in anhydrousdimethylformamide (5ml) affording the title product as the hydrochloride(0.5 g, 80%) m/z, 455.2 (M+H)⁺.

Example 345-Ethoxycarbonyl-7-(3-((dimethylamino)methyl)phenyl)-1-phenylbenzimidazole

This was prepared analogously to5-Ethoxycarbonyl-7-(3-(morpholin-4-yl-methyl)phenyl)-1-phenylbenzimidazolefrom 5-ethoxycarbonyl-7-(3-(chloromethyl)phenyl)-1-phenylbenzimidazole(0.50 g, 1.28 mmol) and dimethylamine (approximately 2 ml) in anhydrousdimethylformamide (5 ml). The crude product was triturated in diethylether to afford the title product as an off-white solid (0.139, 25%)m/z, 400.2 (M+H)⁺.

Example 35 5-Cyano-7-(3-cyanophenyl)-1-phenylbenzimidazole

5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol),3-cyanophenylboronic acid (73 mg, 0.5 mmol), ethanol (3.0 ml) andpotassium carbonate (138 mg, 1.0 mmol) were combined and the mixture wasstirred at reflux overnight. The solvent was removed under reducedpressure and the crude product was purified on a 2 9 silica Isolute® SPEcolumn, eluting with dichloromethane/methanol (95:5). The eluent wasconcentrated under reduced pressure and the crude product was purifiedby reverse-phase prep LCMS to give the title compound (9.3 mg, 6%) m/z,321.2 (M+H)⁺.

Example 36 5-Cyano-7-(4-nitrophenyl)-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 4-nitrophenylboronic add (84 mg, 0.5 mmol), ethanol (3.0ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by asimilar procedure afforded the title compound (56 mg, 33%) m/z, 341.0(M+H)⁺.

Example 37 7-(4-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole

This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58mg, 0.05 mmol), 4-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol(3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar mannerto 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification bya similar procedure afforded the title compound (66 mg, 37%) m/z, 353.0(M+H)⁺.

Example 38 7-(3-Acetamidophenyl)-1-phenyl-5-trifluoromethylbenzimidazole

A solution of 7-(3-aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole(0.32 g, 0.9 mmol) in acetic anhydride (3 ml) was stirred at ambienttemperature for one hour. Saturated, aqueous sodium carbonate was addedand the resultant mixture was extracted with ethyl acetate. This organicextract was washed with water and brine, successively, dried overmagnesium sulphate, concentrated under reduced pressure and purified bycolumn chromatography on silica gel eluting with a mixture ofdichloromethane and methanol (97:3, v/v) to afford the desired product(0.27 g, 76%) m/z, 396.1 (M+H)⁺.

Example 39 O-Methyl 7-(3-acetmidophenyl)-5-formyl-1-Phenylbenzimidazoleoxime

This was prepared from O-Methyl7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime (70 mg, 0.2 mmol)by acetylation with acetic anhydride under standard conditions to affordthe off-white solid product (44 mg, 57%) m/z, 385.2 (M+H)⁺.

Example 40 O-Methyl7-(3-(dimethylamino)phenyl)-5-formyl-1-phenylbenzimidazole oxime

This was prepared analogously to O-Methyl7-(3-aminophenyl)-5-formyl-1-phenylbenzimidazole oxime from5-cyano-7-(3-(dimethylamino)phenyl)-1-phenylbenzimidazole (0.4 g, 1.2mmol), Raney Ni (0.6 g) in a mixture of formic acid (6 ml) and water (3ml). The intermediate aldehyde was used without purification and treatedwith O-methyl hydroxylamine to afford the title product (30 mg, 14%)m/z, 371.2 (M+H)⁺.

Example 41 5-Cyano-7-(4-diethylaminomethylphenyl)-1-phenylbenzimidazoletrifluoroacetic acid salt

5-Cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole was preparedfrom 5-cyano-7-iodo-1-phenylbenzimidazole (1.0 g, 2.90 mmol),4-hydroxymethylphenylboronic acid (440 mg, 2.90 mmol),tetrakis(triphenylphosphine)palladium(0) (330 mg, 2.90 mmol) andpotassium carbonate (2 M in water, 2.9 ml, 800 mg, 5.8 mmol) in toluene(8.0 ml) and ethanol (2.0 ml) using the method described for5-cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole.5-Cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole was obtained asa white solid (711 mg) m/z, 326.3 (M+H)⁺.

5-Cyano-7-(4-methanesulphonylmethylphenyl)-1-phenylbenzimidazole wasprepared from 5-cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole(500 mg, 1.54 mmol), diisopropylethylamine (0.82 ml, 4.62 mmol) andmethanesulphonyl chloride (0.13 ml, 1.69 mmol) in dichloromethane (10ml) using the method described for5-cyano-7-(3-methanesulphonylmethylphenyl)-1-phenylbenzimidazole. Thecrude solution (approximately 0.14 M of product) was used directly inthe next stage.

The title compound was prepared from5-cyano-7-(4-methanesulphonylmethylphenyl)-1-phenylbenzimidazole (2.0ml, 0.14 M solution in dichloromethane) and diethylamine (0.041 ml, 0.40mmol) using the method described for5-cyano-7-(3-diethylaminomethylphenyl)-1-phenylbenzimidazole.Purification by prep LCMS gave the title compound as a clear, colourlessglass (38 mg, 7%) m/z, 381.4 (M+H)⁺.

Example 42 7-(4-Benzamidyl)-5-cyano-1-Phenylbenzimidazoletrifluoroacetic acid salt

This was prepared in a similar manner to5-cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole, with 70 hreflux before removal of solvent using nitrogen to give an oily residue.The residue was taken up in dimethylsulphoxide (2 ml) and eluted througha prep LCMS column to give, after removal of the solvent, the desiredproduct as a glass (99 mg, 44%) m/z, 339.3 (M+H)⁺.

Example 43 7-(3-Acetamidophenyl)-5-hydroxymethyl-1-phenylbenzimidazole,and 7-(3-Ethylaminophenyl)-5-hydroxymethyl-1-Phenylbenzimidazole

To a stirred solution of7-(3-acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole (1.0 g,2.51 mmol) in anhydrous tetrahydrofurane (50ml) was added lithiumaluminum hydride (0.2 g, 5 mmol). The resultant mixture was stirred atambient temperature in a nitrogen atmosphere for 6 days. Water wasadded, and the resultant mixture was extracted with ethyl acetate. Theorganic extract was washed with brine, dried over magnesium sulphate andconcentrated under reduced pressure. The concentrate waschromatographied on silica gel eluting with a mixture of methanol andethyl acetate (1:19 v/v) to afford the two title products:7-(3-acetamidophenyl)-5-hydroxymethyl-1-phenylbenzimidazole (0.38 g,42%) m/z, 358.2 (M+H)+, and7-(3-ethylaminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole (0.20 g,23%) m/z, 344.2 (M+H)⁺.

Example 447-(3-Dimethylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole and7-(3-Methylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole

To a solution of7-(3-aminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole (1.0 g, 2.8mmol) in tetrahydrofurane (5 ml) was added iodomethane (1.6 ml, 25.7mmol) and triethylamine (2.3 ml, 16.6 mmol) and the resultant mixturewas stirred at 40° C. overnight, whereafter it was partitioned betweenethyl acetate and brine. The organic phase was dried over magnesiumsulphate and concentrated under reduced pressure. The concentrate waschromatographied on silica gel eluting with a mixture of ethyl acetateand petroleum ether (1:1 v/v). Removal of solvent from the appropriateeluate fractions afforded7-(3-dimethylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole (83mg, 8%) m/z, 382.2 (M+H)⁺, and7-(3-methylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole (26mg,3%) m/z, 368.1 (M+H)⁺.

Example 451-Phenyl-7-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-5-trifluoromethylbenzimidazole

To a suspension of7-(3-(hydroxymethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (6.0g, 16.3 mmol) in anhydrous toluene (60 ml) was added thionyl chloride(1.43 ml, 19.5 mmol) and the mixture was stirred at ambient temperaturefor 30 min. The solvent was removed by evaporation under reducedpressure, and7-(3-(chloromethyl)phenyl-phenyl-5-trifluoromethylbenzimidazoleprecipitated from the residue upon trituration with ethyl acetate, 5.65g (90%).

To a cooled (0° C.) solution of the above product (0.97 g, 2.5 mmol) inNMP (5 ml) was added 1-methylpiperazine (0.84 ml, 7.5 mmol) and theresultant mixture was stirred at ambient temperature overnight and thenpartitioned between ethyl acetate and water. The organic layer waswashed with aqueous calcium chloride (3 M) and water, successively,dried over magnesium sulphate and evaporated under reduced pressure toafford the desired product, which precipitated upon trituration in amixture of diethyl ether and petroleum ether (1:5, v/v), 0.2 g (18%),m/z, 451.2 (M+H)⁺.

Example 467-(3-(1-Morpholinylmethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogeously to the above product from7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97g, 2.5 mmol) and morpholine (0.74 ml, 7.5 mmol) in NMP (5 ml) to yield0.81 g (74%), m/z, 382.1 (M+H)⁺.

Example 477-(3-((Dimethylamino)methyl)Phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogeously to the above product from7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97g, 2.5 mmol) and dimethyl amine (2 ml) in NMP (5 ml) to yield 0.54 g(55%), m/z, 396.2 (M+H)⁺.

Example 485-Cyano-7-(4-(2-(4-morpholino)ethoxy)phenyl)-1-phenylbenzimidazoletrifluoroacetic acid salt

5-Cyano-7-(4-hydroxyphenyl)-1-phenylbenzimidazole (62 mg, 0.2 mmol),4-(2-hydroxyethyl)morpholine (39 mg, 0.3 mmol), diisopropylazodicarboxylate (59 μl, 61 mg, 0.3 mmol), dichloromethane (2.0 ml), andresin-bound triphenylphosphine (360 mg, 0.3 mmol) were addedsequentially to a tube and shaken at ambient temperature for 70 h. Theliquid was filtered off and the resin washed twice with dichloromethane(2 ml) and twice with methanol (2 ml). The combined filtrates wereevaporated and the residue was dissolved in dimethylsulphoxide (2 ml)and eluted through a prep LCMS column to give, after removal of thesolvent, the desired product as a glass (15 mg, 14%) m/z, 425.5 (M+H)⁺.

Example 49 7-(3-(N-Methylacetamido)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

To a solution of7-(3-acetamidophenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.35 g,0.88 mmol) in anhydrous tetrahydrofurane (5 ml) was added sodium hydride(0.09 g 60% dispersion in mineral oil, 2.2 mmol). The resultant mixturewas stirred for one hour at ambient temperature, whereafter iodomethane(0.44 ml, 7 mmol) was added and the temperature was raised to 40° C. for30 min. The cooled mixture was partitioned between water and ethylacetate. The organic layer was washed with water, dried over magnesiumsulphate and concentrated under reduced pressure. The concentrate waseluted through silica gel with a mixture of dichloromethane and methanol(97:3, v/v). Removal of solvent from the eluate afforded the titleproduct (0.13 g, 36%) m/z, 410.1 (M+H)⁺.

Example 50 1-Phenyl-7-(4-pyridyl)-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.0 g, 7.5mmol), pyridine 4-boronic acid (1.38 g, 11.2 mmol), 1,3-propanediol (2.7ml, 37.3 mmol), potassium carbonate (5.2 g, 37.3 mmol) andbis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in amixture of dimethoxyethane (30 ml) and water (15 ml) was stirred atreflux for 5 days. The cooled reaction mixture was concentrated underreduced pressure, and the concentrate was partitioned between water andethyl acetate. The organic phase was dried and concentrated underreduced pressure, and the concentrate was purified by columnchromatography on silica gel eluting with a mixture of ligroin and ethylacetate (1:1 v/v). The product was isolated as a yellowish solid byevaporation of solvent from the eluate (1.55 g, 61%) m/z, 340.1 (M+H)⁺.

Example 515-(Hydroxymethyl)-1-phenyl-7-(3-trifluoromethoxyphenyl)benzimidazole

A mixture of 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (6.5 g, 16.6mmol), 3-trifluoromethoxyphenyl boronic acid (5.12 g, 24.9 mmol),1,3-propanediol (6 ml, 82.9 mmol), potassium carbonate (11.4 g, 82.9mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol)in a mixture of dimethoxyethane (60 ml) and water (30 ml) was stirred atreflux for 30 minutes. The cooled reaction mixture was poured into waterand the crude5-ethoxycarbonyl-1-phenyl-7-(3-trifluoromethoxyphenyl)benzimidazole (6.6g, 93%) was filtered off, washed with water and air-dried.

To a solution of this product (0.5 g, 1.17 mmol) in anhydrous THF (20ml) was added lithium aluminum hydride (0.04 g, 1.17 mmol) and theresultant mixture was stirred in a nitrogen atmosphere at ambienttemperature for 6 days. Aqueous sodium bicarbonate was added and themixture was extracted with ethyl acetate. This extract was dried overmagnesium sulphate, concentrated under reduced pressure and theconcentrate was eluted through silica gel with ethyl acetate. The purefractions were concentrated and the title product was isolated as thehydrochloride by addition of etheral hydrochloric acid to thisconcentrate (0.24 g, 49%) m/z, 385.1 (M+H)⁺.

Example 52 7-(4-pyridyl N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole

To a solution of 7-(4-pyridyl)-1-phenyl-5trifluoromethylbenzimidazole(1.25 g, 3.69 mmol) in dichloromethane (50 ml) was added mCPBA (1.0 g,5,9 mmol) and the resultant mixture was stirred at ambient temperaturefor 3 days. The solvent was removed by evaporation and the residue waspartitioned between saturated, aqueous sodium carbonate and ethylacetate. The organic layer was dried over magnesium sulphate andconcentrated under reduced pressure. The concentrate was eluted throughsilica gel with a mixture of ethyl acetate and methanol (9:1, v/v) toafford the title product (1.15 g, 88%) m/z, 356.1 (M+H)⁺.

Example 53 7-(3-chloro-4pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole

A solution of 7-(4-pyridylN-oxide)-1-phenyl-5-trifluoromethylbenzimidazole (0.8 g, 2.25 mmol) inphosphoroxychloride (3 ml) was stirred at 80° C. for 3 hours. To thecooled solution was added saturated, aqueous sodium carbonate and theresultant mixture was extracted with ethyl acetate. The organic extractwas dried over magnesium sulphate and concentrated under reducedpressure. The concentrate was purified by column chromatography onsilica gel eluting with a mixture of ethyl acetate and ligroin (1:1,v/v). The title product was obtained as the hydrochloride by addition ofetheral hydrochloric acid (2 M) to the concentrated eluate (0.44 g, 48%)m/z, 374.1 (M+H)⁺.

Example 547-(3-chloro-4-pyridyl-N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogously to 7-(4-pyridylN-oxide)-1-phenyl-5-trifluoromethylbenzimidazole from7-(3-chloro-4-pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.45 g,1.20 mmol) and mCPBA (0.74 g, 4.3 mmol) in dichloromethane (20 ml) toafford the title product (0.12 g, 26%) m/z, 390.1 (M+H)⁺.

Example 55 7-(3-Acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (7.38 g, 19mmol), 3-acetylphenyl boronic acid (4.67 g, 28.5 mmol), 1,3-propanediol(6.8 ml, 95 mmol), potassium carbonate (13.1 g, 95 mmol) andbis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in amixture of dimethoxyethane (60 ml) and water (30 ml) was stirred atreflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixturewas filtered through a pad of Celite and the filter was rinsed withethyl acetate. The organic layer was collected, dried over magnesiumsulphate and concentrated under reduced pressure. The title productprecipitated upon addition of diethyl ether to the concentrate (6.17 g,85%) m/z, 381.1 (M+H)⁺.

Example 56 7-(3-Fluorophenyl)-1-Phenyl-5-trifluorophenylbenzimidazole

This was prepared analogeously to the above product from7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (0.78 g, 2 mmol)3-fluorophenyl boronic acid (0.42 g, 3 mmol), 1,3-propanediol (0.72 ml,10 mmol), potassium carbonate (1.38 g, 10 mmol) andbis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in amixture of dimethoxyethane (6.4 ml) and water (3.2 ml). The titleproduct was crystallised from ligroin (0.61 g, 86%) m/z, 373.2 (M+H)⁺.

Example 57 3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylicacid methyl ester

Methyl acrylate (2.7 ml, 30 mmol),7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.48 g, 10 mmol),triethylamine (2.79 ml, 20 mmol), palladium acetate (45 mg, 0.2 mmol),tri-o-tolylphosphine (161 mg, 0.53 mmol) and acetonitrile (50 ml) werecombined and the mixture heated at reflux under an argon atmosphere for17 h. The mixture was cooled, filtered through Dicalite and the filtratewas concentrated under reduced pressure. Crystals formed and wereisolated by filtration and dried to give the title compound (3.2 9,92%), m/z 347.0 (M+H)⁺.

Example 58 3-(6-Cyano-3-phenyl-3H-benzimidazol-4-yl)acrylic acid methylester

Methyl acrylate (0.27 ml, 3 mmol), 5-cyano-7-iodo-1-phenylbenzimidazole(346 mg, 1.0 mmol), triethylamine (0.28 ml, 2 mmol) palladium acetate(4.5 mg, 0.02 mmol), tri-o-tolylphosphine (16.1 mg, 0.05 mmol) andacetonitrile (5 ml) were combined in Reactivial™. The mixture was heatedunder reflux under an argon atmosphere for 17 h. The mixture was cooled,filtered through Dicalite and the filtrate was concentrated underreduced pressure. Crystals formed and were isolated by filtration anddried to give the title compound (250 mg, 83%), m/z 304.2 (M+H)⁺.

Example 59 7-(4-Morpholinyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of aniline (1.12 ml, 12.3 mmol) and2,3-difluoro-1-nitro-5-trifluoromethylbenzene (2.8 g, 12.3 mmol) washeated at 110° C. for 24 h. Dichloromethane was added and the resultingprecipitate filtered off. The filtrate was concentrated under reducedpressure then redissolved in ethyl acetate. 10% Palladium on carbon (0.5g, Degussa) was added and the resulting suspension hydrogenated at 5 barfor 1 h. The reaction mixture was filtered through celite, washed withethyl acetate and, the filtrate concentrated under reduced pressure.Formic acid (10 mL) was added and the mixture heated at 110° C. for 24h. Concentration under reduced pressure gave7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole as a purple solid (3.0g, 87%) m/z, 281.0 (M+H)⁺.

To 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole (400 mg, 1.4 mmol)was added morpholine (1 ml, 1.1 mmol) and the mixture heated in aPersonal Chemistry Smith Creator™ microwave for ten 30 minute periods at245° C. The residue was chromatographed over silica gel to give thetitle compound as a solid (50 mg, 10%) m/z, 348.0 (M+H)⁺.

Example 60 5-t-Butyl-7-(3-dimethylaminophenyl)-1-phenylbenzimidazoletrifluoroacetic acid salt

5-t-Butyl-7-iodo-1-phenylbenzimidazole (94 mg, 0.25 mmol), toluene (1.5ml), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.0125 mmol),3-dimethylaminophenylboronic acid (41 mg, 0.25 mmol), ethanol (1.5 ml)and potassium carbonate (1 M in water, 0.5 ml, 69 mg, 0.5 mmol) wereadded sequentially to a Smith Process Vial™ under nitrogen andirradiated for 70 s at 180° C. (150 W initial power) using a PersonalChemistry Smith Creator™ microwave. The tube was blown dry with nitrogenand the solid residue dissolved in dimethylsulphoxide (2 ml) and elutedthrough a prep LCMS column to give, after removal of the solvent, thedesired product as a glass (102 mg, 42%) m/z, 370.5 (M+H)⁺.

Example 617-(3-(1-Methoxyethyl)Phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

To a stirred solution of7-(3-(1-hydroxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole(0.9 g, 2.4mmol) in anhydrous DMF (5 ml) was added sodium hydride (0.15g 60% dispersion in mineral oil, 3.5 mmol) at ambient temperature. Whenthe evolution of hydrogen had ceased iodomethane (0.25 ml, 2.6 mmol) wasadded and stirring was continued for 15 min. Four volumes of water wasadded and the resultant mixture was extracted with ethyl acetate. Thisextract was washed twice with aqueous calcium chloride (3 M), dried overmagnesium sulphate and evaporated under reduced pressure. The residuewas eluted through silica gel with a mixture of ethyl acetate andpetroleum ether (2:3, v/v). Trituration of the concentrated eluate inligroin afforded the title product (0.35 g, 37%) m/z, 397.2 (M+H)⁺.

Example 627-(1-Methyl-5-indolyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 2.5mmol), 1-methyl-5-indolyl boronic acid (0.65 g, 3.73 mmol),1,3-propanediol (0.9 ml, 12.4 mmol), potassium carbonate (1.71 g, 12.4mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol)in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred atreflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixturewas partitioned between ethyl acetate and water and the organic layerwas dried over magnesium sulphate and evaporated under reduced pressure.The residue was triturated in ethanol to afford the title product as anoff-white solid (0.82 g, 84%) m/z, 392.1 (M+H)⁺.

Example 637-(3-(1-Hydroxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

To a suspension of7-(3-acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.95 g, 2.5mmol) in ethanol (10 ml) was added sodium borohydride (0.1 g, 2.6 mmol)and the resultant mixture was stirred at 60° C. for 20 min. The cooledreaction mixture was concentrated under reduced pressure and theconcentrate was partitioned between ethyl acetate and water. The organiclayer was dried over magnesium sulphate and concentrated to a smallvolume (1-2 ml) under reduced pressure. The title product precipitatedupon addition of ligroin to the concentrate (0.65 g, 68%) m/z, 383.1(M+H)⁺.

Example 64 7-(3-Furyl)-1-phenyl-5-trifluoromethylbenzimidazole

A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (0.5 g, 1.25mmol), 3-furane boronic acid (0.2 g, 1.87 mmol), 1,3-propanediol (0.45ml, 6.2 mmol), potassium carbonate (0.86 g, 6.2 mmol) andbis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in amixture of dimethoxyethane (10 ml) and water (15 ml) was stirred atreflux in a nitrogen atmosphere for 30 min. The cooled reaction mixturewas partitioned between ethyl acetate and water and the organic layerwas dried over magnesium sulphate and evaporated under reduced pressure.The residue was triturated in diethyl ether to afford the title productas an off-white solid (0.22 g, 54%) m/z, 329.1 (M+H)⁺.

Example 65N,N-Diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-yl)prop-2-en-1-one.The oily residue was purified by flash chromatography over silica gel(eluted with dichloromethane/methanol 0.5-2.5% gradient) to afford thetitle compound as a white solid (300 mg, 53%), m/z 388.0 (M+H)⁺.

Example 661-(4-Methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one

To a stirred suspension of aluminium trichloride (1.46 mmol, 195 mg) indichloromethane (3 ml) was added dropwise N-methylpiperazine (1.83 mmol,203 l). The resultant mixture was stirred for 0.5 h and to this, asolution of 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylicacid methyl ester (0.73 mmol, 250 mg) was added dropwise. The resultantmixture stirred for 16 h at 60° C. Upon cooling, aqueous sodiumcarbonate (5%, 5 ml) was added and the mixture was shaken. The organiclayer was isolated by filtration through a hydrophobic frit andevaporated under reduced pressure to give an off-white solid.Recrystallisation from diethyl ether afforded the title compound as awhite powder (160 mg, 53%), m/z 415.2 (M+H)⁺.

Example 673-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl-1-piperidinylprop-2-en-1-one

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-oneto afford the title compound as a white solid (150 mg, 51%), m/z 400.0(M+H)⁺.

Example 681-(4-Morpholinyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)Prop-2-en-1-one

This was prepared from3-(3-phenyl-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-oneto afford the title compound as a white solid (350 mg, 60%), m/z 402.2(M+H)⁺.

Example 691-(4-Methyl-[1,4]-hexahydrodiazepin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol4-yl)prop-2-en-1-oneto afford the title compound as a white solid (80 mg, 26%), m/z 429.2(M+H)⁺.

Example 70N-(2-Cyanoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford, afterremoval of the solvent, the title compound as a white solid (13 mg, 5%),m/z 385.0 (M+H)⁺.

Example 713-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol4-yl)-N-propylacrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford, afterremoval of the solvent, the title compound as a white solid (16 mg, 6%),m/z 374.0 (M+H)⁺.

Example 72N-(2-Dimethylaminoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol4-yl)prop-2-en-1-one.The oily residue was purified by flash chromatography over silica gel(eluted with dichloromethane/methanol 2-5% gradient) to afford the titlecompound as a white solid (29 mg, 5%), m/z 403.4 (M+H)⁺.

Example 733-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-(4-trifluoromethyl-piperidin-1-yl)prop-2-en-1-one

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford, afterremoval of the solvent, the title compound as a white solid (40 mg,12%), m/z 468.2 (M+H)⁺.

Example 747-(3-(2-Hydroxy-2-propyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole

To an ice-cooled solution of7-(3-acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole ((0.76 g, 2.0mmol) in anhydrous tetrahydrofurane (5 ml) was added a solution ofmethylmagnesium bromide (1.0 ml, 3 M) dropwise over 5 min. The ice-bathwas removed and the mixture was stirred at ambient temperature for 4hours. Aqueous ammonium chloride, and subsequently ethyl acetate, wasadded.

The organic layer was dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by column chromatographyeluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v)to afford the title product (0.26 g, 33%) m/z, 397.2 (M+H)⁺.

Example 757-(4-Hydroxypiperidinyl)-1-phenyl-5-trifluoromethylbenzimidazole

To 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole (500 mg, 1.78 mmol)was added piperidine (2 g, 23 mmol) and the mixture heated in a PersonalChemistry Smith Creator™ microwave for two 30 minute periods at 245° C.The residue was chromatographed over silica gel to give the titlecompound as a solid (350 mg, 54%) m/z, 362.2 (M+H)⁺.

Example 76 7-(3-Fluorophenyl)-5-methyl-1-Phenylbenzimidazoletrifluoroacetic acid salt

This was prepared in a similar manner to5-t-butyl-7-(3-dimethylaminophenyl)-1-phenylbenzimidazole, using7-iodo-5-methyl-1-phenylbenzimidazole (84 mg, 0.25 mmol) to realise thedesired product (57 mg, 27%) m/z, 303.3 (M+H)⁺.

Example 777-(4-Hydroxybut-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole

To a stirred solution of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole(9.7 g, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.9 g, 5mmol) in pyrrolidine (75 ml) was added a solution of 3-butyn-1-ol (7.0g, 0.1 mol) in pyrrolidine (75 ml), then copper (I) iodide (475 mg, 2.5mmol). The resulting solution was heated to 75° C. with stirring undernitrogen. After 2.5 h the reaction mixture was allowed to cool, treatedwith saturated aqueous ammonium chloride and extracted with diethylether. The combined organic extracts were dried over anhydrous sodiumsulphate and the solvent removed under reduced pressure to leave aresidue (13.6 g). This residue was flash chromatographed over silica gel(eluted with dichloromethane/diethyl ether 4:1) to give the desiredproduct (3.95 g, 48%) m/z, 330.8 (M+H)⁺.

Example 787-(1-(1-(4-Hydroxyethylpiperazinyl)ethyl)-1-methylamino)-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

To 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole (2.4 g, 8.6 mmol)was added N-methylethanolamine (9.6 ml, 12 mmol) and the mixture heated(in batches) in a Personal Chemistry Smith Creator™ microwave for four30 minute periods at 245° C. The reaction mixture was partitionedbetween dichloromethane and water. The organic layer was separated,dried and concentrated under reduced pressure. The residue waschromatographed over silica gel to give7-[1-(hydroxyethyl)-1-methylamino]-1-phenyl-5-trifluoromethylbenzimidazoleas a solid (1.2 g, 42%) m/z, 336.0 (M+H)⁺.

To a solution of7-[1-(hydroxyethyl)-1-methylamino]-1-phenyl-5-trifluoromethylbenzimidazole(1.2 g, 3.6 mmol) in dichloromethane at 0° C. was added triethylamine(0.5 ml, 3.6 mmol) then methanesulphonyl chloride (0.28 ml, 3.6 mmol).The reaction mixture was stirred at 0° C. for 2 h then allowed to warmto room temp and stirred for a further 20 h. The resulting residue waschromatographed over silica gel to give7-[1-(2-methylsulphonylhydroxy)ethyl-1-methylamino]-1-phenyl-5-trifluoromethylbenzimidazoleas a solid (1.0 g, 67%).

To a solution of7-[1-(2-methylsulphonylhydroxy)ethyl-1-methylamino]-1-phenyl-5-trifluoromethylbenzimidazole(28 mg, 0.067 mmol) in dimethylsulphoxide (0.4 ml) at 0° C. was addedN-methylpiperazine (0.1 ml, 0.9 mmol). The reaction was stirred at 70°C. for 18 h then allowed to warm to room temp and stirred for a further20 h. Purification by prep LCMS gave the title compound as a gum (5.6mg, 18%) m/z, 448.0 (M+H)⁺.

Example 797-(1-(1-(4-Methylpiperazinyl)ethyl)-1-methyl)amino-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

To a solution of7-[1-(2-methylsulphonylhydroxy)ethyl-1-methylamino]-1-phenyl-5-trifluoromethylbenzimidazole(28 mg, 0.067 mmol) in dimethylsulphoxide (0.4 ml) at 0° C. was addedN-methylpiperazine (0.1 ml). The reaction was stirred at 70° C. for 18 hthen allowed to warm to room temp and stirred for a further 20 h.Purification by prep LCMS gave the title compound as a gum (9.9 mg, 35%)m/z, 418.0 (M+H)⁺.

Example 807-(3-(4-Morpholino)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

7-(3-Hydroxyprop-1-ynyl1-phenyl-5-trifluoromethylbenzimidazole (32 mg,0.1 mmol), toluene (0.6 ml), and diisopropylethylamine (52 μl, 39 mg,0.3 mmol) were added sequentially to a Smith Process Vial™, cooled to−15° C. and methanesulphonyl chloride (9 μl, 13 mg, 0.11 mmol) added.The mixture was stirred for 0.5 h as it warmed to ambient temperaturethen stirred for 1.5 h. The mixture was then cooled to −15° C. andmorpholine (11 μl, 11 mg, 0.12 mmol) added. This mixture was stirred for0.5 h as it warmed to ambient temperature then stirred for 0.5 h. Themixture was then irradiated for 1800 s at 200° C. (300 W initial power)using a Personal Chemistry Smith Creator™ microwave. The tube was blowndry with nitrogen and the solid residue dissolved in dimethylsulphoxide(2 ml) and eluted through a prep LCMS column to give, after removal ofthe solvent, the desired product as a glass (61 mg, 60%) m/z, 386.1(M+H)⁺.

Example 81N,N-Diethyl-3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)propionamide

Alumina supported formate was prepared according to the procedure ofDanks and Desai (T. N. Danks and B. Desai, Green Chemistry, 2002, 4,179-180). A Smith Process Vial™ was loaded with alumina supportedformate (0.5 g), Wilkinson's catalyst (0.5 mg),N,N-diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide(0.064 mmol, 25 mg) and dimethylsulphoxide (0.5 ml) and was irradiatedfor 600 s at 180° C. using a Personal Chemistry Smith Creator™microwave. The mixture was filtered to remove the solid support and thefiltrate was purified by LCMS to give, after evaporation, the titlecompound as a solid (7.8 mg, 31%), m/z 390.0 (M+H)⁺.

Example 823-(6-tert-Butyl-3-phenyl-3H-benzimidazol4-yl)-1-(piperidin-1-yl)prop-2-en-1-one

5-t-Butyl-7-iodo-1-phenylbenzimidazole was prepared in a similar mannerto 5-cyano-7-iodo-1-phenylbenzimidazole, using4-t-butyl-2,6-dinitrophenol as starting material to realise the desiredproduct (11.75 g, 44%) m/z, 377.2 (M+H)⁺.

The title compound was prepared in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-oneusing 5-t-butyl-7-iodo-1-phenylbenzimidazole as starting material. Theoily residue was purified by preparative LCMS to afford the titlecompound as a white solid (25 mg, 22%), m/z 388.2 (M+H)⁺.

Example 83N-Ethyl-N-isopropyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol4-yl)acrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (7.2 mg, 6%), m/z 402.0 (M+H)⁺.

Example 84N-(1-Methylpiperidin-4-yl)methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamidetrifluoroacetic acid salt

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (32 mg, 25%), m/z 443.0 (M+H)⁺.

Example 85N-Methyl-N-(1-methylpyrrolidin-3-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamidetrifluoroacetic acid salt

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (11.4 mg, 9%), m/z 429.0 (M+H)⁺.

Example 863-(6-tert-Butyl-3-phenyl-3H-benzimidazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)acrylamidetrifluoroacetic acid salt

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (15.3 mg, 12%), m/z 431.0 (M+H)⁺.

Example 877-(4-(Diethylaminobutyl)-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

7-(4-Hydroxybutynyl-phenyl-5-trifluoromethylbenzimidazole (1 g, 3.03mmol), was dissolved in ethyl acetate (20 ml) and a catalytic amount ofDegussa catalyst (palladium, 10 wt. % (dry basis) on activated carbon,containing 50% water) was added. This was treated with hydrogen gas in aBuchi hydrogenator at 5 bar pressure for 18 h. The reaction mixture wasfiltered through celite and evaporated to dryness giving7-(4-hydroxy)butyl-1-phenyl-5-trifluoromethylbenzimidazole a yellow oilwhich crystallised on standing.

7-(4-Hydroxy)butyl-1-phenyl-5-trifluoromethylbenzimidazole (900 mg, 2.7mmol) was dissolved in dichloromethane (20 ml) and triethylamine (1.13ml, 8.1 mmol), cooled to 0° C. Methanesulphonyl chloride (0.3 ml, 2.97mmol), was added and stirred at 0° C. for 3 h. The solvent was removedunder reduced pressure and the resulting solid was triturated with ethylacetate and filtered. The filtrate was evaporated under reduced pressuregiving the mesylate as a yellow oil.

The mesylate (70 mg, 0.17 mmol) was dissolved in ethanol (2 ml) anddiethylamine (0.1 ml, 9.7×10⁻⁴ mol) added. The resulting solution washeated to 60° C. with shaking for 66 h. The reaction mixture waspurified by prep HPLC (acetonitrile/water/trifluoroacetic acid) to givethe title compound (15.9 mg, 19%) m/z, 390.0 (M+H)⁺.

Example 887-(4-((N-(2-Cyanoethyl)-N-methyl)amino)-1-butyl)-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

This was prepared in a similar manner to7-(4-(diethylamino)butyl)-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt using 3-methylaminopropionitrile (0.1 ml, 1.07mmol) to realise the desired product (3.5 mg, 4%) m/z, 401.2 (M+H)⁺.

Example 893-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-(pyrollidin-1-yl)prop-2-en-1-one

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (7.3 mg, 7%), m/z 386.0 (M+H)⁺.

Example 901-(2.5-Dihydropyrrol-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (6.2 mg, 6%), m/z 384.0 (M+H)⁺.

Example 91N-(2-Cyanoethyl)-N-methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide

This was prepared from3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester in a similar manner to1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one.The oily residue was purified by preparative LCMS to afford the titlecompound as a white solid (5.6 mg, 5%), m/z 399.0 (M+H)⁺.

Example 921-Phenyl-7-(3-(1-(1,2,3,6-tetrahydropyridinyl))prop-1-ynyl)-5-trifluoromethylbenzimidazole

This was prepared in a similar manner to7-(3-(4-morpholinyl)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazoleusing 1,2,3,6-tetrahydropyridine in place of morpholine to realise thedesired product (18 mg, 24%) m/z, 382.4 (M+H)⁺.

Example 931-Phenyl-7-(3-(1-piperidinyl)prop-1-ynyl)-5-trifluoromethylbenzimidazole

This was prepared in a similar manner to7-(3-(4-morpholinyl)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazoleusing piperidine in place of morpholine to realise the desired product(13 mg, 17%) m/z, 384.4 (M+H)⁺.

Example 947-[1-(3-Dimethylamino)pyrrolidinyl]-1-phenyl-5-trifluoromethylbenzimidazoletrifluoroacetic acid salt

7-Fluoro-1-phenyl-5-trifluoromethylbenzimidazole (300 mg, 1.07 mmol) and3-(dimethylamino)pyrrolidine (1.7 g, 15 mmol) were heated in a PersonalChemistry Smith Creator™ microwave for three 30 minute periods at 245°C. The reaction mixture was partitioned between dichloromethane andwater. The organic layer was separated, dried and concentrated underreduced pressure. Purification by prep LCMS gave the title compound as asolid (150 mg) m/z, 374.8 (M+H)⁺.

Intermediates

7-Amino-5-cyano-1-phenylbenzimidazole

To a cooled (5° C.) solution of 4-chloro-3,5-dinitrobenzonitril (50 g,0.22 mol) in anhydrous DMF (200 ml) was added aniline (40 ml, 0.44 mol)dropwise over 1 hour. The resultant mixture was stirred for additionally1 hour at 0° C. and then poured into ice-water (1400 g). The precipitatewas filtered off, washed with water and air-dried to affordN-phenyl-4-cyano-2,6-dinitroaniline, quantitatively.

To a stirred suspension of N-phenyl- 4-cyano-2,6-dinitroaniline (16.4 g,57.8 mmol) and SnCl₂, 2H₂O (130.5 g, 0.58 mol) in abs. ethanol (300 ml)was added formic acid (90 ml) dropwise at ambient temperature. Thereaction is exothermic. The reaction was allowed to proceed at ambientconditions overnight. The resultant mixture was rendered alkaline byaddition of saturated, aqueous sodium carbonate and was filtered throughCelite. The filtrate was extracted with dichloromethane. The organicextract was dried over magnesium sulphate and evaporated under reducedpressure. The residue was triturated in cold ethyl acetate to leave thetitle product (8.65 g, 64%).

7-Amino-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared in analogy with 7-amino-5-cyano-1-phenylbenzimidazoleusing 4-chloro-3,5-dinitrobenzotrifluoride as the starting material (11g, 75%)

5-Cyano-7-iodo-1-phenylbenzimidazole

A suspension of 7-Amino-5-cyano-1-phenylbenzimidazole (12.5 g, 53.4mmol) in hydrochloric acid (90 ml, 25% w/v) was diazotised with asolution of sodium nitrite (3.7 g, 53.4 mmol) in water (20 ml). Theresultant mixture was stirred for 30 min at 0° C. whereafter a solutionof potassium iodide (14.2 g, 85.5 mmol) in water (40 ml) was addeddropwise. Stirring was continued for 10 min at 0° C., and then thetemperature was raised to 80° C. for 30 min. After cooling, aqueoussodium sulphite (1M) was added and the resultant mixture was extractedwith dichloromethane. Column chromatographic work-up of the dried andconcentrated organic extract afforded the title product (6.5 g, 35%)

7-iodo-1-phenyl-5-trifluoromethylbenzimidazole

This was prepared analogously to 5-cyano-7-iodo-1-phenylbenzimidazolefrom 4-chloro-3,5-dinitrobenzotrifluoride (6.8 g, 67%)

5-Ethoxycarbonyl-7-iodo-1-phenylbenzimidazole

This was prepared analogously to 5-cyano-7-iodo-1-phenylbenzimidazolefrom ethyl 4-chloro-3,5-dinitrobenzoate (0.7 g, 50%)

5t-Butyl-7-iodo-1-phenylbenzimidazole

This was prepared in a similar manner to5-cyano-7-iodo-1-phenylbenzimidazole, using 4-t-butyl-2,6-dinitrophenolas starting material to realise the desired product (11.75 g, 44%) m/z,377.2 (M+H)⁺.

7-iodo-5-methyl-1-phenylbenzimidazole

This was prepared in a similar manner to5-cyano-7-iodo-1-phenylbenzimidazole, using 4-methyl-2,6-dinitrophenolas starting material to realise the desired product (1.45 g, 16%) m/z,335.1 (M+H)⁺.

7-(3-Hydroxyprop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole

To a stirred solution of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole(9.7 g, 25 mmol) and tetrakis (triphenylphosphine)palladium(0) (2.9 g, 5mmol) in pyrrolidine (75 ml) was added a solution of 2-propyn-1-ol (5.6g, 0.1 mol) in pyrrolidine (75 ml), then copper (I) iodide (475 mg, 2.5mmol). The resulting solution was heated to 75° C. with stirring undernitrogen. After 5 h the reaction mixture was allowed to cool, treatedwith saturated aqueous ammonium chloride and extracted with diethylether. The combined organic extracts were dried over anhydrous sodiumsulphate and the solvent removed under reduced pressure to leave aresidue (14.5 g). This residue was flash chromatographed over silica gel(eluted with dichloromethane/diethyl ether 4:1) to give the desiredproduct (2.53 g, 32%) m/z, 316.8 (M+H)⁺.

Test Methods

Test Method 1

In vitro inhibition of ³H-flunitrazepam (³H-FNM) Binding

The GABA recognition site and the benzodiazepine modulatory unit canselectively be labelled with ³H-flunitrazepam.

Tissue Preparation

Preparations are performed at 0-4° C. unless otherwise indicated.Cerebral cortex from male Wistar rats (150-200 g) is homogenised for5-10 sec in 20 ml Tris-20 HCl (30 mM, pH 7.4) using an Ultra-Turraxhomogeniser. The suspension is centrifuged at 27,000×g for 15 min andthe pellet is washed three times with buffer (centrifuged at 27,000×gfor 10 min). The washed pellet is homogenized in 20 ml of buffer andincubated on a water bath (37° C.) for 30 min to remove endogenous GABAand then centrifuged for 10 min at 27,000×g. The pellet is thenhomogenized in buffer and centrifuged for 10 min at 27,000×g. The finalpellet is resuspended in 30 ml buffer and the preparation is frozen andstored at −20° C.

Assay

The membrane preparation is thawed and centrifuged at 2° C. for 10 minat 27,000×g. The pellet is washed twice with 20 ml 50 mM Tris-citrate,pH 7.1 using an Ultra-Turrax homogeniser and centrifuged for 10 min at27,000×g. The final pellet is resuspended in 50 mM Tris-citrate, pH 7.1(500 ml buffer per g of original tissue), and then used for bindingassays. Aliquots of 0.5 ml tissue are added to 25 μl of test solutionand 25 μl of ³H-FNM (1 nM, final concentration), mixed and incubated for40 min at 2° C. Non-specific binding is determined using Clonazepam (1μM, final concentration). After incubation the samples are added 5 ml ofice-cold buffer and poured directly onto Whatman GF/C glass fibrefilters under suction and immediately washed with 5 ml ice-cold buffer.The amount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

Results

25-75% inhibition of specific binding must be obtained, beforecalculation of an IC₅₀.

The test value will be given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-FNM by 50%).${IC}_{50} = {\left( {{{applied}\quad{test}\quad{substance}\quad{concentration}},{\mu M}} \right) \times \frac{1}{\left( {\frac{C_{o}}{C_{x}} - 1} \right)}}$

where

C_(o) is specific binding in control assays, and

C_(x) is the specific binding in the test assay.

(The calculations assume normal mass-action kinetics).

Test results from these experiments with a number of compounds of theinvention are shown in Table 1 below. TABLE 1 Test compound Compound ofIn vitro binding Example: IC₅₀ (μM) 6 0.0042 10 0.018 12 0.030 23 0.03833 0.019 41 0.027 51 0.012 57 0.046 65 0.020 75 0.042 80 0.18 81 0.03888 0.10 92 0.048 94 0.090

1. A compound of general formula (I):

or an N-oxide thereof, or any of its isomers or any mixture of itsisomers, or a pharmaceutically acceptable salt thereof, wherein R⁵ ishalo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, alkoxy,-alkyl-OR^(a), —CH═N—O—R^(a) or —(C═O)—O-alkyl; wherein R^(a) ishydrogen or alkyl;

wherein one of R^(b) and R^(c) is hydrogen; and the other of R^(b) andR^(c) is hydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl,trifluoromethoxy, alkyl, alkoxy, alkylcarbonyl or —NR^(d)—(C═O)—R^(e);wherein the alkyl and alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of: hydroxy, alkoxy,halo, and —NR′R″; R^(d) and R^(e) independently of each other areselected from hydrogen and alkyl; R′ and R″ independently of each otherare selected from hydrogen and alkyl; —NR^(f)R^(g), —alkyl-NR^(f)R^(g),—(C═O)—NR^(f)R^(g), —O—NR^(f)R^(g); —O-alkyl-NR^(f)R^(g);—NR^(h)-alkyl-NR^(f)R^(g); wherein R^(h) is hydrogen or alkyl; R^(f) andR^(g) independently of each other are hydrogen or alkyl; or R^(f) andR^(g) together with the nitrogen to which they are attached form a 5- to7-membered heterocyclic ring, which heterocyclic ring may optionallycomprise as a ring member, one oxygen atom, and/or one additionalnitrogen atom, and/or one carbon-carbon double bond, and/or onecarbon-nitrogen bond; and which heterocyclic ring may optionally besubstituted with trifluoromethyl, alkyl, hydroxyalkyl, or —NR′R″; wherein R′ and R″ independently of each other are hydrogen or alkyl; orR^(b) and R^(c) together represent —O—CH₂—O—;  or R⁷ is—NR^(h)—(C═O)—R^(i), —N═CH—R^(i), or —C≡C—R^(i); wherein R^(h) ishydrogen or alkyl; and R^(i) is alkyl or phenyl, which alkyl or phenylis optionally substituted with hydroxy, trifluoromethyl, cyano or alkyl;or —NR^(j)R^(k), -alkyl-NR^(j)R^(k), —CH═CH—(C═O)—NR^(j)R^(k),—CH═CH—(C═O)—O-alkyl, -alkyl-(C═O)—NR^(j)R^(k), or —C≡C—CH₂—NR^(j)R^(k);wherein R^(j) and R^(k) independently of each other are selected fromthe group consisting of hydrogen, alkyl, -alkyl-CN, -alkyl-R′R″ and-alkyl-R^(l); wherein R′ and R″ independently of each other are hydrogenor alkyl; R^(l) is a 5- to 7-membered heterocyclic ring comprising onenitrogen atom,  which heterocyclic ring may optionally comprise as aring member, one oxygen atom, and/or one additional nitrogen atom,and/or one carbon-carbon double bond, and/or one carbon-nitrogen bond;and which heterocyclic ring may optionally be substituted withtrifluoromethyl, alkyl, hydroxyalkyl, or —NR′R″;  wherein R′ and R″independently of each other are hydrogen or alkyl; or R^(j) and R^(k)together with the nitrogen to which they are attached form a 5- to7-membered heterocyclic ring, which heterocyclic ring may optionallycomprise as a ring member, one oxygen atom, and/or one additionalnitrogen atom, and/or one carbon-carbon double bond, and/or onecarbon-nitrogen bond; and which heterocyclic ring may optionally besubstituted with trifluoromethyl, alkyl, hydroxy, hydroxyalkyl, or—NR′R″;  wherein R′ and R″ independently of each other are hydrogen oralkyl; or R⁷ is a heteroaryl group which heteroaryl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano,nitro, alkyl, and alkoxy; with the proviso that the compound is not7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,7-(3-Pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole,1,7-Diphenyl-5-trifluoromethylbenzimidazole,7-benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole, or7-amino-1-phenyl-5-trifluoromethylbenzimidazole.
 2. The compound ofclaim 1, wherein R⁵ is selected from the group of methyl, tertbutyl,trifluoromethyl, hydroxymethyl, cyano, ethoxycarbonyl, —CH═N—OH, and—CH═N—O—CH₃.
 3. The compound of claim 1, wherein R⁷ is

wherein one of R^(b) and R^(c) is hydrogen; and the other of R^(b) andR^(c) is hydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl,trifluoromethoxy, alkyl, alkoxy, alkylcarbonyl or —NR^(d)—(C═O)—R^(e);wherein the alkyl and alkoxy are optionally substituted with one or moresubstituents selected from the group consisting of: hydroxy, alkoxy,halo, and —NR′R″; —NR^(f)R^(g), -alkyl-NR^(f)R^(g), —(C═O)—NR^(f)R^(g),—O—NR^(f)R^(g); —O-alkyl-NR^(f)R^(g); —NR^(h)-alkyl -NR^(f)R^(g);wherein R^(d), R^(e), R^(f), R^(g), R^(h), R′ and R″ are as defined inclaim
 1. 4. The chemical compound of claim 1, wherein R⁷ is3,4-methylenedioxyphenyl.
 5. The chemical compound of claim 1, whereinR⁷ is R⁷ is —NR^(h)—(C═O)—R^(i), —N═CH—R^(i), or —C≡C—R^(i); whereinR^(h) is hydrogen or alkyl; and R^(i) is alkyl or phenyl, which alkyl orphenyl is optionally substituted with hydroxy, trifluoromethyl, cyano oralkyl; or —NR^(j)R^(k), -alkyl-NR^(j)R^(k), —CH═CH—(C═O)—NR^(j)R^(k),—CH═CH—(C═O)—O-alkyl, -alkyl-(C═O)—NR^(J)R^(k), or —C≡C—CH₂—NR^(j)R^(k);wherein R^(j) and R^(k) independently of each other are selected fromthe group consisting of hydrogen, alkyl, -alkyl-CN, -alkyl-R′R″ and-alkyl-R¹; wherein R′ and R″ independently of each other are hydrogen oralkyl; R^(l) is a 5- to 7-membered heterocyclic ring comprising onenitrogen atom, which heterocyclic ring may optionally comprise as a ringmember, one oxygen atom, and/or one additional nitrogen atom, and/or onecarbon-carbon double bond, and/or one carbon-nitrogen bond; and whichheterocyclic ring may optionally be substituted with trifluoromethyl,alkyl, hydroxyalkyl, or —NR′R″;  wherein R′ and R″ independently of eachother are hydrogen or alkyl; or R^(j) and R^(k) together with thenitrogen to which they are attached form a 5- to 7-membered heterocyclicring, which heterocyclic ring may optionally comprise as a ring member,one oxygen atom, and/or one additional nitrogen atom, and/or onecarbon-carbon double bond, and/or one carbon-nitrogen bond; and whichheterocyclic ring may optionally be substituted with trifluoromethyl,alkyl, hydroxy, hydroxyalkyl, or —NR′R″; wherein R′ and R″ independentlyof each other are hydrogen or alkyl.
 6. The chemical compound of claim1, wherein R⁷ is indolyl, pyridyl or furyl optionally substituted haloor methyl. (1-Methyl-5-indolyl, pyridin-4-yl, pyridin-3-yl or3-chloro-pyridin-4-yl.).
 7. The compound of claim 1, which is7-(3-Chlorophenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime; O-Methyl7-(3-Aminophenyl)-5-formyl-1-phenylbenzimidazole oxime;7-(N-benzylideneamino)-1-phenyl-5-trifluoromethylbenzimidazole;7-(N-(4-cyanobenzylidene)amino)-1-phenyl-5-trifluoromethylbenzimidazole;7-(N-(3-cyanobenzylidene)amino)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Aminophenyl)-5-cyano-1-phenylbenzimidazole;7-(3-(Hydroxymethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;1-Phenyl-7-(3-(1,2,3,6-tetrahydropyridine-1-ylmethyl)phenyl)-5-trifluoromethylbenzimidazole;7-(3-Acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole;7-(3-Aminophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole;5-(Ethoxycarbonyl)-7-(3-(hydroxymethyl)phenyl)-1-phenylbenzimidazole;7-(3-Cyanophenyl)-1-phenyl-5-trifluorophenylbenzimidazole;5-Cyano-7-(3-nitrophenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-((1-methylpiperazin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-(diethylaminomethyl)phenyl)-1-phenylbenzimidazole;7-(3-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole;5-Cyano-7-(4-methoxyphenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-methoxyphenyl)-1-phenylbenzimidazole;5-Cyano-7-(4-cyanophenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-fluorophenyl)-1-phenylbenzimidazole;5-Cyano-7-(4-hydroxyphenyl)-1-phenylbenzimidazole;5-Cyano-7-[3-(dimethylamino)phenyl]-1-phenylbenzimidazole;5-Cyano-7-(3,4-methylenedioxyphenyl)-1-phenylbenzimidazole;5-Cyano-7-(pyridin-4-yl)-1-phenylbenzimidazole;7-(3-Aminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;5-Ethoxycarbonyl-7-(3-((morpholin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;5-Ethoxycarbonyl-7-(3-((1-methylpiperazin-4-yl)methyl)phenyl)-1-phenylbenzimidazole;5-Ethoxycarbonyl-7-(3-((dimethylamino)methyl)phenyl)-1-phenylbenzimidazole;5-Cyano-7-(3-cyanophenyl)-1-phenylbenzimidazole;5-Cyano-7-(4-nitrophenyl)-1-phenylbenzimidazole;7-(4-Acetamidophenyl)-5-cyano-1-phenylbenzimidazole;7-(3-Acetamidophenyl)-1-phenyl-5-trifluoromethylbenzimidazole; O-Methyl7-(3-acetmidophenyl)-5-formyl-1-phenylbenzimidazole oxime; O-Methyl7-(3-(dimethylamino)phenyl)-5-formyl-1-phenylbenzimidazole oxime;5-Cyano-7-(4-diethylaminomethylphenyl)-1-phenylbenzimidazole;7-(4-Benzamidyl)-5-cyano-1-phenylbenzimidazole;7-(3-Acetamidophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;7-(3-Ethylaminophenyl)-5-hydroxymethyl-1-phenylbenzimidazole;7-(3-Dimethylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole;7-(3-Methylaminophenyl)-5-trifluoromethyl-1-phenylbenzimidazole;1-Phenyl-7-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-5-trifluoromethylbenzimidazole;7-(3-(1-Morpholinylmethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-((Dimethylamino)methyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;5-Cyano-7-(4-(2-(4-morpholino)ethoxy)phenyl)-1-phenylbenzimidazole;7-(3-(N-Methylacetamido)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;1-Phenyl-7-(4-pyridyl)-5-trifluoromethylbenzimidazole;5-(Hydroxymethyl)-1-phenyl-7-(3-trifluoromethoxyphenyl)benzimidazole;7-(4-pyridyl N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-chloro-4-pyridyl)-1phenyl-5-trifluoromethylbenzimidazole;7-(3-chloro-4-pyridyl-N-oxide)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Fluorophenyl)-1-phenyl-5-trifluorophenylbenzimidazole;3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methylester; 3-(6-Cyano-3-phenyl-3H-benzimidazol-4-yl)acrylic acid methylester; 7-(4-Morpholinyl)-1-phenyl-5-trifluoromethylbenzimidazole;5-t-Butyl-7-(3-dimethylaminophenyl)-1-phenylbenzimidazole;7-(3-(1-Methoxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(1-Methyl-5-indolyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-(1-Hydroxyethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Furyl)-1-phenyl-5-trifluoromethylbenzimidazole;N,N-Diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;1-(4-Methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-piperidinylprop-2-en-1-one;1-(4-Morpholinyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;1-(4-Methyl-[1,4]-hexahydrodiazepin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;N-(2-Cyanoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-N-propylacrylamide;N-(2-Dimethylaminoethyl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-(4-trifluoromethylpiperidin-1-yl)prop-2-en-1-one;7-(3-(2-Hydroxy-2-propyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(4-Hydroxypiperidinyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-Fluorophenyl)-5-methyl-1-phenylbenzimidazole;7-(4-Hydroxybut-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(1-(1-(4-Hydroxyethylpiperazinyl)ethyl)-1-methylamino)-1-phenyl-5-trifluoromethylbenzimidazole;7-(1-(1-(4-Methylpiperazinyl)ethyl)-1-methyl)amino-1-phenyl-5-trifluoromethylbenzimidazole;7-(3-(4-Morpholino)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole;N,N-Diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)propionamide;3-(6-tert-Butyl-3-phenyl-3H-benzimidazol-4-yl)-1-(piperidin-1-yl)prop-2-en-1-one;N-Ethyl-N-isopropyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;N-(1-Methylpiperidin-4-yl)methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;N-Methyl-N-(1-methylpyrrolidin-3-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;3-(6-tert-Butyl-3-phenyl-3H-benzimidazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)acrylamide;7-(4-(Diethylamino)butyl)-1-phenyl-5-trifluoromethylbenzimidazole;7-(4-((N-(2-Cyanoethyl)-N-methyl)amino)-1-butyl)-1-phenyl-5-trifluoromethylbenzimidazole;3-(3-Phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)-1-(pyrollidin-1-yl)prop-2-en-1-on1-(2,5-Dihydropyrrol-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one;N-(2-Cyanoethyl)-N-methyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide;1-Phenyl-7-(3-(1-(1,2,3,6-tetrahydropyridinyl))prop-1-ynyl)-5-trifluoromethylbenzimidazole;1-Phenyl-7-(3-(1-piperidinyl)prop-1-ynyl)-5-trifluoromethylbenzimidazole;7-[1-(3-Dimethylamino)pyrrolidinyl]-1-phenyl-5-trifluoromethylbenzimidazole;or an N-oxide thereof, or any of its isomers or any mixture of itsisomers, or a pharmaceutically acceptable salt thereof.
 8. Apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of claim 1, or the compound7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,7-(3-Pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole,1,7-Diphenyl-5-trifluoromethylbenzimidazole,7-benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole, or7-amino-1-phenyl-5-trifluoromethylbenzimidazole, or an N-oxide thereof,or any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.
 9. Use of thechemical compound of claim 1, or the compound7-(3-Aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,7-(3-Pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole,1,7-Diphenyl-5-trifluoromethylbenzimidazole,7-benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole, or7-amino-1-phenyl-5-trifluoromethylbenzimidazole, or an N-oxide thereofor any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament.
 10. A method for treatment, prevention or alleviation of adisease or a disorder or a condition of a mammal, including a human,which disease, disorder or condition is responsive to modulation of theGABA_(A) receptor complex in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective mount of a compound according toclaim 1 or the compound7-(3-aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole,7-(3-pyridyl)-1-phenyl-5-trifluoromethylbenzimidazole,1,7-diphenyl-5-trifluoromethylbenzimidazole,7-benzoylamino-1-phenyl-5-trifluoromethylbenzimidazole, or7-amino-1-phenyl-5-trifluoromethylbenzimidazole, or an N-oxide thereof,or any of its isomers or any mixture of its isomers or apharmaceutically acceptable salt thereof.
 11. The method according toclaim 10, wherein the disease, disorder or condition is anxietydisorder, panic disorder with or without agoraphobia, agoraphobiawithout history of panic disorder, phobia, animal phobia, social phobia,obsessive-compulsive disorder, generalized or substance-induced anxietydisorder, stress disorder, post-traumatic and acute stress disorder,sleep disorder, memory disorder, convulsive disorder, epilepsy, febrileconvulsions in children, premenstrual syndrome, muscle spasm orspasticity, effects of substance abuse or dependency, effects of alcoholwithdrawal, or disorder of circadian rhythm.
 12. The method according toclaim 10, for inducing and maintaining anaesthesia, sedation and musclerelaxation or for pre-medication prior to anaesthesia or minorprocedures such as endoscopy, including gastric endoscopy.